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Kai J, Su J, You Y, Liang X, Huang H, Fang J, Chen Q. Identifying key palmitoylation-associated genes in endometriosis through genomic data analysis. BMC Womens Health 2025; 25:161. [PMID: 40188118 PMCID: PMC11972508 DOI: 10.1186/s12905-025-03697-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 03/28/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Palmitoylation, a post-translational lipid modification, has garnered increasing attention for its role in inflammatory processes and tumorigenesis. Emerging evidence suggests a potential association between palmitoylation and inflammatory responses in the pathogenesis of endometriosis. However, the precise mechanistic interplay remains elusive, necessitating further investigation. METHODS This study integrated transcriptomic analysis and Mendelian randomization (MR) to identify a causal gene set implicated in endometriosis. Differentially expressed genes (DEGs) were first identified in the training dataset using the limma package in R. Weighted gene co-expression network analysis (WGCNA) was subsequently performed, leveraging Single Sample Gene Set Enrichment Analysis (ssGSEA)-derived scores of palmitoylation-related genes (PRGs) as phenotypic traits to identify key modular genes. The intersection of these key modular genes with DEGs yielded a refined gene set. Machine learning algorithms were then applied to further optimize gene selection, followed by external validation, immune infiltration analysis, RNA network construction, and exploration of potential targeted drug candidates. RESULTS Through a rigorous screening process, VRK1, GALNT12, and RMI1 emerged as key genes associated with palmitoylation, exhibiting significant downregulation in endometriosis samples (P < 0.05), indicative of a potential protective role. Immune infiltration analysis further revealed strong correlations between these genes and M2 macrophages as well as resting Natural Killer (NK) cells. Additionally, investigations into the targeted RNA network and drug association profiling provided novel insights, laying the groundwork for future high-quality validation studies. CONCLUSIONS This study employed a comprehensive analytical framework to identify palmitoylation-associated key genes in endometriosis. The integration of immunoinfiltration analysis, RNA network construction, and drug association profiling offers valuable insights for advancing clinical diagnostics, disease monitoring, and therapeutic development in endometriosis.
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Affiliation(s)
- Jinyan Kai
- Department of Clinical Medical Laboratory, The Affiliated Second Hospital of Xiamen Medical College, Xiamen, Fujian, China
| | - Jiaqi Su
- Department of Clinical Medical Laboratory, The Affiliated Second Hospital of Xiamen Medical College, Xiamen, Fujian, China
| | - Yinping You
- Department of Pathology, The Affiliated Second Hospital of Xiamen Medical College, Xiamen, Fujian, China
| | - Xiaoliang Liang
- Department of Clinical Medical Laboratory, The Affiliated Second Hospital of Xiamen Medical College, Xiamen, Fujian, China
| | - Haitao Huang
- Department of Microbiology, Guilin Medical University, Guilin, Guangxi, China
| | - Jie Fang
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qiong Chen
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (Originally Named "Shanghai First People's Hospital"), Shanghai, China.
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2
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La Vecchia M, Sala G, Sculco M, Aspesi A, Dianzani I. Genetics, diet, microbiota, and metabolome: partners in crime for colon carcinogenesis. Clin Exp Med 2024; 24:248. [PMID: 39470880 PMCID: PMC11522171 DOI: 10.1007/s10238-024-01505-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 10/15/2024] [Indexed: 11/01/2024]
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant tumors worldwide, with a multifactorial etiology encompassing genetic, environmental, and life-style factors, as well as the intestinal microbiota and its metabolome. These risk factors often work together in specific groups of patients, influencing how CRC develops and progresses. Importantly, alterations in the gut microbiota act as a critical nexus in this interplay, significantly affecting susceptibility to CRC. This review highlights recent insights into unmodifiable and modifiable risk factors for CRC and how they might interact with the gut microbiota and its metabolome. Understanding the mechanisms of these interactions will help us develop targeted, precision-medicine strategies that can adjust the composition of the gut microbiota to meet individual health needs, preventing or treating CRC more effectively.
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Affiliation(s)
- Marta La Vecchia
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Gloria Sala
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Marika Sculco
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Anna Aspesi
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Irma Dianzani
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy.
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3
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Ferreira JR, Caldeira J, Sousa M, Barbosa MA, Lamghari M, Almeida-Porada G, Gonçalves RM. Dynamics of CD44 + bovine nucleus pulposus cells with inflammation. Sci Rep 2024; 14:9156. [PMID: 38644369 PMCID: PMC11033282 DOI: 10.1038/s41598-024-59504-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/11/2024] [Indexed: 04/23/2024] Open
Abstract
Intervertebral Disc (IVD) degeneration has been associated with a chronic inflammatory response, but knowledge on the contribution of distinct IVD cells, namely CD44, to the progression of IVD degeneration remains elusive. Here, bovine nucleus pulposus (NP) CD44 cells were sorted and compared by gene expression and proteomics with the negative counterpart. NP cells were then stimulated with IL-1b (10 ng/ml) and dynamics of CD44 gene and protein expression was analyzed upon pro-inflammatory treatment. The results emphasize that CD44 has a multidimensional functional role in IVD metabolism, ECM synthesis and production of neuropermissive factors. CD44 widespread expression in NP was partially associated with CD14 and CD45, resulting in the identification of distinct cell subsets. In conclusion, this study points out CD44 and CD44-based cell subsets as relevant targets in the modulation of the IVD pro-inflammatory/degenerative cascade.
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Affiliation(s)
- J R Ferreira
- I3S-Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal
- Cell & Gene Therapy Safety, Clinical Pharmacology & Safety Science, R&D, AstraZeneca, Molndal, Sweden
| | - J Caldeira
- I3S-Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal
| | - M Sousa
- I3S-Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Porto, Portugal
| | - M A Barbosa
- I3S-Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal
| | - M Lamghari
- I3S-Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal
| | - G Almeida-Porada
- WFIRM-Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina, USA
| | - R M Gonçalves
- I3S-Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Porto, Portugal.
- INEB-Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal.
- Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal.
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Cao J, Liu Z, Yuan J, Luo Y, Wang J, Liu J, Bo H, Guo J. Subgrouping testicular germ cell tumors based on immunotherapy and chemotherapy associated lncRNAs. Heliyon 2024; 10:e24320. [PMID: 38298718 PMCID: PMC10827771 DOI: 10.1016/j.heliyon.2024.e24320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 12/01/2023] [Accepted: 01/07/2024] [Indexed: 02/02/2024] Open
Abstract
Testicular germ cell tumors (TGCT) are the most common reproductive system malignancies in men aged 15-44 years, accounting for 95 % of all testicular tumors. Our previous studies have been shown that long non-coding RNAs (lncRNAs), such as LINC00313, TTTY14 and RFPL3S, were associated with development of TGCT. Subgrouping TGCT according to differential expressed lncRNAs and immunological characteristics is helpful to comprehensively describe the characteristics of TGCT and implement precise treatment. In this study, the TGCT transcriptome data in The Cancer Genome Atlas Program (TCGA) database was used to perform consensus clustering analysis to construct a prognostic model for TGCT. TGCT was divided into 3 subtypes C1, C2, and C3 based on the differentially expressed lncRNAs. C1 subtype was sensitive to chemotherapy drugs, while the C2 subtype was not sensitive to chemotherapy drugs, and C3 subtype may benefit from immunotherapy. We defined the C1 subtype as epidermal progression subtype, the C2 subtype as mesenchymal progression subtype, and the C3 subtype as T cell activation subtype. Subgrouping based on differentially expressed genes (DEGs) and immunological characteristics is helpful for the precise treatment of TGCT.
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Affiliation(s)
- Jian Cao
- Hunan Cancer Hospital, Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University, Changsha, 410013, Hunan, China
| | - Zhizhong Liu
- Hunan Cancer Hospital, Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University, Changsha, 410013, Hunan, China
| | - Junbin Yuan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Yanwei Luo
- Department of Blood Transfusion, the Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Jinrong Wang
- Department of Urology, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan, China
| | - Jianye Liu
- Department of Urology, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan, China
| | - Hao Bo
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, Hunan, China
- NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, 410078, Hunan, China
| | - Jie Guo
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, Hunan, China
- China National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- International Science and Technology Innovation Cooperation Base for Early Clinical Trials of Biological Agents in Hunan Province, Changsha, Hunan, China
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5
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Zhou L, Du K, Dai Y, Zeng Y, Luo Y, Ren M, Pan W, Liu Y, Zhang L, Zhu R, Feng D, Tian F, Gu C. Metabolic reprogramming based on RNA sequencing of gemcitabine-resistant cells reveals the FASN gene as a therapeutic for bladder cancer. J Transl Med 2024; 22:55. [PMID: 38218866 PMCID: PMC10787972 DOI: 10.1186/s12967-024-04867-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/06/2024] [Indexed: 01/15/2024] Open
Abstract
Bladder cancer (BLCA) is the most frequent malignant tumor of the genitourinary system. Postoperative chemotherapy drug perfusion and chemotherapy are important means for the treatment of BLCA. However, once drug resistance occurs, BLCA develops rapidly after recurrence. BLCA cells rely on unique metabolic rewriting to maintain their growth and proliferation. However, the relationship between the metabolic pattern changes and drug resistance in BLCA is unclear. At present, this problem lacks systematic research. In our research, we identified and analyzed resistance- and metabolism-related differentially expressed genes (RM-DEGs) based on RNA sequencing of a gemcitabine-resistant BLCA cell line and metabolic-related genes (MRGs). Then, we established a drug resistance- and metabolism-related model (RM-RM) through regression analysis to predict the overall survival of BLCA. We also confirmed that RM-RM had a significant correlation with tumor metabolism, gene mutations, tumor microenvironment, and adverse drug reactions. Patients with a high drug resistance- and metabolism-related risk score (RM-RS) showed more active lipid synthesis than those with a low RM-RS. Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect.
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Affiliation(s)
- Lijie Zhou
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Unit of Day Surgery Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Kaixuan Du
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Unit of Day Surgery Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yiheng Dai
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Unit of Day Surgery Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Youmiao Zeng
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Unit of Day Surgery Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yongbo Luo
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengda Ren
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wenbang Pan
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuanhao Liu
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lailai Zhang
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ronghui Zhu
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Dapeng Feng
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fengyan Tian
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Chaohui Gu
- Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Unit of Day Surgery Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Bilyalov A, Danishevich A, Nikolaev S, Vorobyov N, Abramov I, Pismennaya E, Terehova S, Kosilova Y, Primak A, Stanoevich U, Lisica T, Shipulin G, Gamayunov S, Kolesnikova E, Khatkov I, Gusev O, Bodunova N. Novel Pathogenic Variants in Hereditary Cancer Syndromes in a Highly Heterogeneous Cohort of Patients: Insights from Multigene Analysis. Cancers (Basel) 2023; 16:85. [PMID: 38201513 PMCID: PMC10778304 DOI: 10.3390/cancers16010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.
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Affiliation(s)
- Airat Bilyalov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Anastasiia Danishevich
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Sergey Nikolaev
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Nikita Vorobyov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Ivan Abramov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
- The Federal State Budgetary Scientific Institution “Izmerov Research Institute of Occupational Health”, 105275 Moscow, Russia
| | | | - Svetlana Terehova
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Yuliya Kosilova
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Anastasiia Primak
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Uglesha Stanoevich
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Tatyana Lisica
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical and Biological Agency, 119435 Moscow, Russia
| | - German Shipulin
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical and Biological Agency, 119435 Moscow, Russia
| | - Sergey Gamayunov
- Nizhny Novgorod Regional Oncologic Hospital, 603163 Nizhny Novgorod, Russia
| | - Elena Kolesnikova
- Nizhny Novgorod Regional Oncologic Hospital, 603163 Nizhny Novgorod, Russia
| | - Igor Khatkov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Oleg Gusev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Life Improvement by Future Technologies (LIFT) Center, 121205 Moscow, Russia
| | - Natalia Bodunova
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
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Krueger KE. Neo-Darwinian Principles Exemplified in Cancer Genomics. Mol Cancer Res 2023; 21:1251-1260. [PMID: 37721477 DOI: 10.1158/1541-7786.mcr-23-0247] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/13/2023] [Accepted: 09/14/2023] [Indexed: 09/19/2023]
Abstract
Within the last two decades, the advent of next-generation sequencing accompanied by single-cell technologies has enabled cancer researchers to study in detail mutations and other genetic aberrations that transpire during transformation of cells to a neoplastic state. This article covers the insights gained through these extensive studies where neo-Darwinian principles can be inferred to play roles throughout neoplastic transformation. The cells promoted during cancer development exhibit cancer hallmarks combined with the related enabling characteristics as outlined by Hanahan and Weinberg, analogous to natural selection and survival of the fittest. Selection of driver mutations that inactivate proteins encoded by tumor suppressor genes differs in profound ways from mutations that activate tumor promoter proteins. In most cases, the later stages of cancer development are characterized by sudden, extensive damage to chromosomes in a process that is not Darwinian in nature. Nevertheless, cells that survive these cataclysmic events remain subject to Darwinian selection promoting clones exhibiting the greatest rates of progression. Duplications of chromosomal segments containing oncogenes, deletions of segments harboring tumor suppressor genes, or distinctive chromosomal rearrangements are often found in cells progressing into later stages of cancer. In summary, the technological developments in genome sequencing since the start of the century have given us clear insights into genomic alterations promoting tumor progression where neo-Darwinian mechanisms of clonal selection can be inferred to play a primary role.
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Aasted MK, Groen AC, Keane JT, Dabelsteen S, Tan E, Schnabel J, Liu F, Lewis HGS, Theodoropulos C, Posey AD, Wandall HH. Targeting Solid Cancers with a Cancer-Specific Monoclonal Antibody to Surface Expressed Aberrantly O-glycosylated Proteins. Mol Cancer Ther 2023; 22:1204-1214. [PMID: 37451822 PMCID: PMC10543972 DOI: 10.1158/1535-7163.mct-23-0221] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/14/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Most current immunotherapeutic targets are tumor-associated antigens that are also found in healthy tissues and often do not display sufficient cancer selectivity to be used as targets for potent antibody-based immunotherapeutic treatments, such as chimeric antigen receptor (CAR) T cells. Many solid tumors, however, display aberrant glycosylation that results in expression of tumor-associated carbohydrate antigens that are distinct from healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes within existing or novel glycoprotein targets may provide the cancer selectivity needed for immunotherapy of solid tumors. However, to date only a few such glycopeptide epitopes have been targeted. Here, we used O-glycoproteomics data from multiple cell lines to identify a glycopeptide epitope in CD44v6, a cancer-associated CD44 isoform, and developed a cancer-specific mAb, 4C8, through a glycopeptide immunization strategy. 4C8 selectively binds to Tn-glycosylated CD44v6 in a site-specific manner with low nanomolar affinity. 4C8 was shown to be highly cancer specific by IHC of sections from multiple healthy and cancerous tissues. 4C8 CAR T cells demonstrated target-specific cytotoxicity in vitro and significant tumor regression and increased survival in vivo. Importantly, 4C8 CAR T cells were able to selectively kill target cells in a mixed organotypic skin cancer model having abundant CD44v6 expression without affecting healthy keratinocytes, indicating tolerability and safety.
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Affiliation(s)
- Mikkel K.M. Aasted
- Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | | | - John T. Keane
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sally Dabelsteen
- Department of Oral Pathology, School of Dentistry, University of Copenhagen, Copenhagen, Denmark
| | - Edwin Tan
- GO-Therapeutics, One Broadway, Cambridge, Massachusetts
| | | | - Fang Liu
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hyeon-Gyu S. Lewis
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Avery D. Posey
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania
| | - Hans H. Wandall
- Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
- GO-Therapeutics, One Broadway, Cambridge, Massachusetts
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Abbass MA, Plesec T, Church JM. A Different Way to Think About Syndromes of Hereditary Colorectal Cancer. Dis Colon Rectum 2023; 66:1339-1346. [PMID: 37163656 DOI: 10.1097/dcr.0000000000002772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
BACKGROUND Hereditary colorectal cancer is an increasingly complex field in which the commoner syndromes are being augmented by rarer genetic presentations contributing to familial polyposis and colorectal cancer. Coming to grips with the complexity is difficult because of the phenotypic and genotypic overlap between syndromes. OBJECTIVE This study aimed to describe a new way of thinking about syndromes of hereditary colorectal cancer based on their embryonic tissue of origin. DATA SOURCES Articles were searched through PubMed and MEDLINE. STUDY SELECTION The terms "hereditary colorectal cancer," "syndromes of hereditary colorectal cancer," and "hereditary polyposis" were used to direct the search. RESULTS Primarily endoderm-derived syndromes were different from mesoderm-derived syndromes in their genetics, molecular biology, histology, and clinical course. LIMITATIONS There is considerable phenotypic and genotypic overlap between syndromes, even when considering embryonic tissue of origin. CONCLUSIONS Thinking about hereditary syndromes of colorectal cancer from the perspective of embryonic tissue of origin provides a fresh look at phenotype and genotype that opens new areas of exploration. UNA FORMA DIFERENTE DE PENSAR SOBRE LOS SNDROMES DEL CNCER COLORRECTAL HEREDITARIO ANTECEDENTES:El cáncer colorrectal hereditario es un campo cada vez más complejo donde los síndromes más comunes se ven aumentados por presentaciones genéticas más raras que contribuyen a la poliposis familiar y al cáncer colorrectal. Hacer frente a esta complejidad resulta difícil debido a la superposición fenotípica y genotípica entre los síndromes.OBJETIVO:En este artículo, describimos una nueva forma de pensar sobre los síndromes de cáncer colorrectal hereditario en función del origen de su tejido embrionario.FUENTES DE DATOS:Se realizaron búsquedas de artículos en Pubmed y Medline.SELECCIÓN DE ESTUDIOS:Se utilizaron los términos "cáncer colorrectal hereditario", "síndromes de cáncer colorrectal hereditario", "poliposis hereditaria" para dirigir la búsqueda.RESULTADOS:Principalmente los síndromes derivados del endodermo fueron diferentes a los síndromes derivados del mesodermo en su genética, biología molecular, histología y curso clínico.LIMITACIONES:Existe una superposición fenotípica y genotípica considerable entre los síndromes, incluso cuando se considera el tejido de origen embrionario.CONCLUSIÓN:Pensar en los síndromes hereditarios del cáncer colorrectal desde la perspectiva del tejido embrionario de origen proporciona una nueva mirada al fenotipo y al genotipo que abre nuevas áreas de exploración. (Traducción-Dr Osvaldo Gauto ).
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Affiliation(s)
- Mohammad Ali Abbass
- Department of Colorectal Surgery, Northwestern University, Chicago, Illinois
| | - Thomas Plesec
- Department of Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
| | - James M Church
- Division of Colorectal Surgery, Columbia University Medical Center, New York, New York
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10
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Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test? Int J Mol Sci 2023; 24:ijms24032137. [PMID: 36768460 PMCID: PMC9916931 DOI: 10.3390/ijms24032137] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/25/2023] Open
Abstract
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
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11
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da Costa V, Mariño KV, Rodríguez-Zraquia SA, Festari MF, Lores P, Costa M, Landeira M, Rabinovich GA, van Vliet SJ, Freire T. Lung Tumor Cells with Different Tn Antigen Expression Present Distinctive Immunomodulatory Properties. Int J Mol Sci 2022; 23:ijms231912047. [PMID: 36233358 PMCID: PMC9570357 DOI: 10.3390/ijms231912047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/22/2022] [Accepted: 09/22/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the first leading cause of cancer-related deaths in the world. Aberrant glycosylation in lung tumors leads to the expression of tumor-associated carbohydrate structures, such as the Tn antigen, consisting of N-acetyl-galactosamine (GalNAc) linked to a serine or threonine residue in proteins (α-GalNAc-O-Ser/Thr). The Tn antigen can be recognized by the Macrophage Galactose/GalNAc lectin (MGL), which mediates various immune regulatory and tolerogenic functions, mainly by reprogramming the maturation of function of dendritic cells (DCs). In this work, we generated two different Tn-expressing variants from the Lewis-type lung murine cancer cell line LL/2, which showed different alterations in the O-glycosylation pathways that influenced the interaction with mouse MGL2 and the immunomodulatory properties of DCs. Thus, the identification of the biological programs triggered by Tn+ cancer cells might contribute to an improved understanding of the molecular mechanisms elicited by MGL-dependent immune regulatory circuits.
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Affiliation(s)
- Valeria da Costa
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
| | - Karina V. Mariño
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 1428, Argentina
| | - Santiago A. Rodríguez-Zraquia
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
| | - María Florencia Festari
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
| | - Pablo Lores
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
| | - Monique Costa
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
| | - Mercedes Landeira
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
| | - Gabriel A. Rabinovich
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 1428, Argentina
| | - Sandra J. van Vliet
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, 1081 HV Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
| | - Teresa Freire
- Laboratorio de Inmunomodulación y Vacunas, Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Montevideo 11800, Uruguay
- Correspondence:
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12
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Syed ZA, Zhang L, Ten Hagen KG. In vivo models of mucin biosynthesis and function. Adv Drug Deliv Rev 2022; 184:114182. [PMID: 35278522 PMCID: PMC9068269 DOI: 10.1016/j.addr.2022.114182] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 12/22/2022]
Abstract
The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies between organisms, certain elements are conserved, including proteins that are heavily decorated with N-acetylgalactosamine-based sugars linked to serines or threonines (O-linked glycosylation). These heavily O-glycosylated proteins, known as mucins, exist in many forms and are able to form hydrated gel-like structures that coat epithelial surfaces. In vivo studies in diverse organisms have highlighted the importance of both the mucin proteins as well as their constituent O-glycans in the protection and health of internal epithelia. Here, we summarize in vivo approaches that have shed light on the synthesis and function of these essential components of mucus.
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Affiliation(s)
- Zulfeqhar A Syed
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892-4370, United States
| | - Liping Zhang
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892-4370, United States
| | - Kelly G Ten Hagen
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892-4370, United States.
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13
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Advances in the Immunomodulatory Properties of Glycoantigens in Cancer. Cancers (Basel) 2022; 14:cancers14081854. [PMID: 35454762 PMCID: PMC9032556 DOI: 10.3390/cancers14081854] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 12/28/2022] Open
Abstract
Simple Summary This work reviews the role of aberrant glycosylation in cancer cells during tumour growth and spreading, as well as in immune evasion. The interaction of tumour-associated glycans with the immune system through C-type lectin receptors can favour immune escape but can also provide opportunities to develop novel tumour immunotherapy strategies. This work highlights the main findings in this area and spotlights the challenges that remain to be investigated. Abstract Aberrant glycosylation in tumour progression is currently a topic of main interest. Tumour-associated carbohydrate antigens (TACAs) are expressed in a wide variety of epithelial cancers, being both a diagnostic tool and a potential treatment target, as they have impact on patient outcome and disease progression. Glycans affect both tumour-cell biology properties as well as the antitumor immune response. It has been ascertained that TACAs affect cell migration, invasion and metastatic properties both when expressed by cancer cells or by their extracellular vesicles. On the other hand, tumour-associated glycans recognized by C-type lectin receptors in immune cells possess immunomodulatory properties which enable tumour growth and immune response evasion. Yet, much remains unknown, concerning mechanisms involved in deregulation of glycan synthesis and how this affects cell biology on a major level. This review summarises the main findings to date concerning how aberrant glycans influence tumour growth and immunity, their application in cancer treatment and spotlights of unanswered challenges remaining to be solved.
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14
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Xia T, Xiang T, Xie H. Update on the role of C1GALT1 in cancer (Review). Oncol Lett 2022; 23:97. [PMID: 35154428 PMCID: PMC8822393 DOI: 10.3892/ol.2022.13217] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/17/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer remains one of the most difficult diseases to treat. In the quest for early diagnoses to improve patient survival and prognosis, targeted therapies have become a hot research topic in recent years. Glycosylation is the most common posttranslational modification in mammalian cells. Core 1β1,3-galactosyltransferase (C1GALT1) is a key glycosyltransferase in the glycosylation process and is the key enzyme in the formation of the core 1 structure on which most complex and branched O-glycans are formed. A recent study reported that C1GALT1 was aberrantly expressed in tumors. In cancer cells, C1GALT1 is regulated by different factors. In the present review, the expression of C1GALT1 in different tumors and its possible molecular mechanisms of action are described and the role of C1GALT1 in cancer development is discussed.
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Affiliation(s)
- Tong Xia
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ting Xiang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hailong Xie
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
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15
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OUP accepted manuscript. Glycobiology 2022; 32:556-579. [DOI: 10.1093/glycob/cwac014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/22/2022] [Accepted: 03/09/2022] [Indexed: 11/12/2022] Open
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16
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Olkinuora AP, Peltomäki PT, Aaltonen LA, Rajamäki K. From APC to the genetics of hereditary and familial colon cancer syndromes. Hum Mol Genet 2021; 30:R206-R224. [PMID: 34329396 PMCID: PMC8490010 DOI: 10.1093/hmg/ddab208] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 11/12/2022] Open
Abstract
Hereditary colorectal cancer (CRC) syndromes attributable to high penetrance mutations represent 9-26% of young-onset CRC cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of CRC susceptibility. With the emergence of next-generation sequencing and associated methods, several predisposition loci have been unraveled, but validation is incomplete. Individuals with cancer-predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how CRC predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.
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Affiliation(s)
- Alisa P Olkinuora
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Päivi T Peltomäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
| | - Kristiina Rajamäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
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17
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Wandall HH, Nielsen MAI, King-Smith S, de Haan N, Bagdonaite I. Global functions of O-glycosylation: promises and challenges in O-glycobiology. FEBS J 2021; 288:7183-7212. [PMID: 34346177 DOI: 10.1111/febs.16148] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022]
Abstract
Mucin type O-glycosylation is one of the most diverse types of glycosylation, playing essential roles in tissue development and homeostasis. In complex organisms, O-GalNAc glycans comprise a substantial proportion of the glycocalyx, with defined functions in hemostatic, gastrointestinal, and respiratory systems. Furthermore, O-GalNAc glycans are important players in host-microbe interactions, and changes in O-glycan composition are associated with certain diseases and metabolic conditions, which in some instances can be used for diagnosis or therapeutic intervention. Breakthroughs in O-glycobiology have gone hand in hand with the development of new technologies, such as advancements in mass spectrometry, as well as facilitation of genetic engineering in mammalian cell lines. High-throughput O-glycoproteomics have enabled us to draw a comprehensive map of O-glycosylation, and mining this information has supported the definition and confirmation of functions related to site-specific O-glycans. This includes protection from proteolytic cleavage, as well as modulation of binding affinity or receptor function. Yet, there is still much to discover, and among the important next challenges will be to define the context-dependent functions of O-glycans in different stages of cellular differentiation, cellular metabolism, host-microbiome interactions, and in disease. In this review, we present the achievements and the promises in O-GalNAc glycobiology driven by technological advances in analytical methods, genetic engineering, and systems biology.
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Affiliation(s)
- Hans H Wandall
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Mathias A I Nielsen
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Sarah King-Smith
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Noortje de Haan
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Ieva Bagdonaite
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
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18
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Supruniuk K, Radziejewska I. MUC1 is an oncoprotein with a significant role in apoptosis (Review). Int J Oncol 2021; 59:68. [PMID: 34278474 PMCID: PMC8360618 DOI: 10.3892/ijo.2021.5248] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/29/2021] [Indexed: 01/10/2023] Open
Abstract
Mucin 1 (MUC1) is a membrane-bound, highly glycosylated protein that is overexpressed in all stages of malignant transformation. Overexpression of MUC1 together with loss of polarization and hypoglycosylation are associated with resistance to apoptosis, which is the process that results in efficient removal of damaged cells. Inhibition of the apoptotic process is responsible for tumor development, tumor progression and drug resistance. MUC1 is considered as an oncogenic molecule that is involved in various signaling pathways responsible for the regulation of apoptosis. Based on this, the aim of the present study was to discuss the involvement of MUC1 in the divergent mechanisms regulating programmed cell death.
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Affiliation(s)
- Katarzyna Supruniuk
- Department of Medical Chemistry, Medical University of Białystok, 15‑222 Białystok, Poland
| | - Iwona Radziejewska
- Department of Medical Chemistry, Medical University of Białystok, 15‑222 Białystok, Poland
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19
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Genetic Predisposition to Numerous Large Ulcerating Basal Cell Carcinomas and Response to Immune Therapy. INTERNATIONAL JOURNAL OF DERMATOLOGY AND VENEROLOGY 2021; 4:70-75. [PMID: 34278326 PMCID: PMC8265835 DOI: 10.1097/jd9.0000000000000170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/18/2021] [Accepted: 05/19/2021] [Indexed: 12/24/2022]
Abstract
Objective: Well-defined germ-line mutations in the PTCH1 gene are associated with syndromic multiple basal cell carcinomas (BCCs). Here, we used whole exome sequencing (WES) to identify the role of patched-1 in patients with multiple, unusually large BCCs. Methods: A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled. WES was used to identify the pathogenic gene locus. Results: Genetic work-up by WES identified a homozygous PTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin. In addition, heterozygous missense mutations were identified in three cancer-associated genes (EPHB2, RET, and GALNT12) in blood cells as well as in lesional and non-lesional skin. We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement. A rapid and sustained response to nivolumab was noted, suggesting that it is an efficacious drug for long-term therapeutic outcome. Conclusion: PTCH1, EPHB2, RET, and GALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple, unusually large BCCs.
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Fernández-Rozadilla C, Álvarez-Barona M, Quintana I, López-Novo A, Amigo J, Cameselle-Teijeiro JM, Roman E, Gonzalez D, Llor X, Bujanda L, Bessa X, Jover R, Balaguer F, Castells A, Castellví-Bel S, Capellá G, Carracedo A, Valle L, Ruiz-Ponte C. Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer. Sci Rep 2021; 11:11135. [PMID: 34045552 PMCID: PMC8159954 DOI: 10.1038/s41598-021-90590-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 05/12/2021] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.
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Affiliation(s)
- C Fernández-Rozadilla
- Grupo de Medicina Xenómica (USC), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain
| | - M Álvarez-Barona
- Grupo de Medicina Xenómica (USC), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain
| | - I Quintana
- Hereditary Cancer Program, Catalan Institute of Oncology, Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Barcelona, Spain
| | - A López-Novo
- Grupo de Medicina Xenómica (USC), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain
| | - J Amigo
- Fundación Publica Galega de Medicina Xenómica, SERGAS, Grupo de Medicina Xenomica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain
| | - J M Cameselle-Teijeiro
- Servicio de Anatomía Patológica, USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico Universitario, Santiago de Compostela, Spain
| | - E Roman
- Gastroenterology Department Hospital de Sant Pau, CIBERehd, Escola Universitària D'Infermeria EUI-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - D Gonzalez
- Patología Digestiva, Hospital de Sant Pau, Barcelona, Spain
| | - X Llor
- Department of Medicine and Cancer Center, Yale University, New Haven, USA
| | - L Bujanda
- Hospital Universitario de Donostia, Instituto Biodonostia, Universidad del Pais Vasco (UPV/EHU), CIBEREHD, San Sebastián, Spain
| | - X Bessa
- Gastroenterology Department, Hospital del Mar, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - R Jover
- Servicio de Medicina Digestiva, Instituto de Investigación Biomédica (ISABIAL), Hospital General Universitario de Alicante, Alicante, Spain
| | - F Balaguer
- Gastroenterology Department, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - A Castells
- Gastroenterology Department, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - S Castellví-Bel
- Gastroenterology Department, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - G Capellá
- Hereditary Cancer Program, Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - A Carracedo
- Fundación Publica Galega de Medicina Xenómica, SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
| | - L Valle
- Hereditary Cancer Program, Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Clara Ruiz-Ponte
- Fundación Publica Galega de Medicina Xenómica, SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
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21
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Heald B, Hampel H, Church J, Dudley B, Hall MJ, Mork ME, Singh A, Stoffel E, Stoll J, You YN, Yurgelun MB, Kupfer SS. Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis. Fam Cancer 2021; 19:223-239. [PMID: 32172433 DOI: 10.1007/s10689-020-00170-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.
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Affiliation(s)
- Brandie Heald
- Sanford R Weiss, MD, Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA.
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - James Church
- Sanford R Weiss, MD, Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
| | - Beth Dudley
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael J Hall
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Maureen E Mork
- Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aparajita Singh
- Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, CA, USA
| | - Elena Stoffel
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jessica Stoll
- Gastrointestinal Cancer Risk and Prevention Clinic, University of Chicago, Chicago, IL, USA
| | - Y Nancy You
- Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sonia S Kupfer
- Gastrointestinal Cancer Risk and Prevention Clinic, University of Chicago, Chicago, IL, USA
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22
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Liu Y, Peng FX. Research progress on O-GlcNAcylation in the occurrence, development, and treatment of colorectal cancer. World J Gastrointest Surg 2021; 13:96-115. [PMID: 33643531 PMCID: PMC7898190 DOI: 10.4240/wjgs.v13.i2.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 12/21/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
For a long time, colorectal cancer (CRC) has been ranked among the top cancer-related mortality rates, threatening human health. As a significant post-translational modification, O-GlcNAcylation plays an essential role in complex life activities. Related studies have found that the occurrence, development, and metastasis of CRC are all related to abnormal O-GlcNAcylation and participate in many critical biological processes, such as gene transcription, signal transduction, cell growth, and differentiation. Recently, nucleotide sugar analogs, tumor-specific carbohydrate vaccine, SIRT1 longevity gene, dendritic cells as targets, and NOTCH gene have become effective methods to induce antitumor therapy. Not long ago, checkpoint kinase 1 and checkpoint kinase 2 were used as therapeutic targets for CRC, but there are still many problems to be solved. With an in-depth study of protein chip, mass spectrometry, chromatography, and other technologies, O-GlcNAcylation research will accelerate rapidly, which may provide new ideas for the research and development of antitumor drugs and the discovery of new CRC diagnostic markers.
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Affiliation(s)
- Yao Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of North Sichuan Medical College, Mianyang 621000, Sichuan Province, China
- Department of Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang 621000, Sichuan Province, China
| | - Fang-Xing Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of North Sichuan Medical College, Mianyang 621000, Sichuan Province, China
- Department of Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang 621000, Sichuan Province, China
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23
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Gaziel-Sovran A, Hernando E. miRNA-mediated GALNT modulation of invasion and immune suppression: A sweet deal for metastatic cells. Oncoimmunology 2021; 1:746-748. [PMID: 22934269 PMCID: PMC3429581 DOI: 10.4161/onci.19535] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Glycosylation is a key process impacting on many aspects of cellular interactions. We recently reported that a miRNA cluster controls glycosylation by directly targeting N-acetylgalactosamine transferases (GALNTs), resulting in increased tumor invasion and immunosuppression. Here we further discuss how defective glycosylation or GALNTs dysregulation may contribute to tumor progression.
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Affiliation(s)
- Avital Gaziel-Sovran
- Department of Pathology; New York University School of Medicine; New York, NY USA
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24
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Bressler KR, Ross JA, Ilnytskyy S, Vanden Dungen K, Taylor K, Patel K, Zovoilis A, Kovalchuk I, Thakor N. Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK). Cell Stress Chaperones 2021; 26:253-264. [PMID: 33123915 PMCID: PMC7736443 DOI: 10.1007/s12192-020-01174-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/13/2020] [Accepted: 10/18/2020] [Indexed: 12/17/2022] Open
Abstract
During the integrated stress response (ISR), global translation initiation is attenuated; however, noncanonical mechanisms allow for the continued translation of specific transcripts. Eukaryotic initiation factor 5B (eIF5B) has been shown to play a critical role in canonical translation as well as in noncanonical mechanisms involving internal ribosome entry site (IRES) and upstream open reading frame (uORF) elements. The uORF-mediated translation regulation of activating transcription factor 4 (ATF4) mRNA plays a pivotal role in the cellular ISR. Our recent study confirmed that eIF5B depletion removes uORF2-mediated repression of ATF4 translation, which results in the upregulation of growth arrest and DNA damage-inducible protein 34 (GADD34) transcription. Accordingly, we hypothesized that eIF5B depletion may reprogram the transcriptome profile of the cell. Here, we employed genome-wide transcriptional analysis on eIF5B-depleted cells. Further, we validate the up- and downregulation of several transcripts from our RNA-seq data using RT-qPCR. We identified upregulated pathways including cellular response to endoplasmic reticulum (ER) stress, and mucin-type O-glycan biosynthesis, as well as downregulated pathways of transcriptional misregulation in cancer and T cell receptor signaling. We also confirm that depletion of eIF5B leads to activation of the c-Jun N-terminal kinase (JNK) arm of the mitogen-activated protein kinase (MAPK) pathway. This data suggests that depletion of eIF5B reprograms the cellular transcriptome and influences critical cellular processes such as ER stress and ISR.
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Affiliation(s)
- Kamiko R Bressler
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
- Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada
| | - Joseph A Ross
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
- Chinook Contract Research Inc., 97 East Lake Ramp NE, Airdrie, Alberta, T4A 2 K4, Canada
| | - Slava Ilnytskyy
- Department of Biological Sciences, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
| | - Keiran Vanden Dungen
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
| | - Katrina Taylor
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
| | - Kush Patel
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
| | - Athanasios Zovoilis
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
- Canadian Centre for Behavioral Neuroscience (CCBN), Department of Neuroscience, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
- Southern Alberta Genome Sciences Centre (SAGSC), University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3 M4, Canada
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada
- Southern Alberta Genome Sciences Centre (SAGSC), University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3 M4, Canada
| | - Nehal Thakor
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada.
- Department of Biological Sciences, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada.
- Canadian Centre for Behavioral Neuroscience (CCBN), Department of Neuroscience, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3M4, Canada.
- Southern Alberta Genome Sciences Centre (SAGSC), University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta, T1K 3 M4, Canada.
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada.
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25
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Mucin-Type O-GalNAc Glycosylation in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1325:25-60. [PMID: 34495529 DOI: 10.1007/978-3-030-70115-4_2] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mucin-type GalNAc O-glycosylation is one of the most abundant and unique post-translational modifications. The combination of proteome-wide mapping of GalNAc O-glycosylation sites and genetic studies with knockout animals and genome-wide analyses in humans have been instrumental in our understanding of GalNAc O-glycosylation. Combined, such studies have revealed well-defined functions of O-glycans at single sites in proteins, including the regulation of pro-protein processing and proteolytic cleavage, as well as modulation of receptor functions and ligand binding. In addition to isolated O-glycans, multiple clustered O-glycans have an important function in mammalian biology by providing structural support and stability of mucins essential for protecting our inner epithelial surfaces, especially in the airways and gastrointestinal tract. Here the many O-glycans also provide binding sites for both endogenous and pathogen-derived carbohydrate-binding proteins regulating critical developmental programs and helping maintain epithelial homeostasis with commensal organisms. Finally, O-glycan changes have been identified in several diseases, most notably in cancer and inflammation, where the disease-specific changes can be used for glycan-targeted therapies. This chapter will review the biosynthesis, the biology, and the translational perspectives of GalNAc O-glycans.
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26
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O-glycan recognition and function in mice and human cancers. Biochem J 2020; 477:1541-1564. [PMID: 32348475 DOI: 10.1042/bcj20180103] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/01/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023]
Abstract
Protein glycosylation represents a nearly ubiquitous post-translational modification, and altered glycosylation can result in clinically significant pathological consequences. Here we focus on O-glycosylation in tumor cells of mice and humans. O-glycans are those linked to serine and threonine (Ser/Thr) residues via N-acetylgalactosamine (GalNAc), which are oligosaccharides that occur widely in glycoproteins, such as those expressed on the surfaces and in secretions of all cell types. The structure and expression of O-glycans are dependent on the cell type and disease state of the cells. There is a great interest in O-glycosylation of tumor cells, as they typically express many altered types of O-glycans compared with untransformed cells. Such altered expression of glycans, quantitatively and/or qualitatively on different glycoproteins, is used as circulating tumor biomarkers, such as CA19-9 and CA-125. Other tumor-associated carbohydrate antigens (TACAs), such as the Tn antigen and sialyl-Tn antigen (STn), are truncated O-glycans commonly expressed by carcinomas on multiple glycoproteins; they contribute to tumor development and serve as potential biomarkers for tumor presence and stage, both in immunohistochemistry and in serum diagnostics. Here we discuss O-glycosylation in murine and human cells with a focus on colorectal, breast, and pancreatic cancers, centering on the structure, function and recognition of O-glycans. There are enormous opportunities to exploit our knowledge of O-glycosylation in tumor cells to develop new diagnostics and therapeutics.
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27
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Dhooge M, Baert-Desurmont S, Corsini C, Caron O, Andrieu N, Berthet P, Bonadona V, Cohen-Haguenauer O, De Pauw A, Delnatte C, Dussart S, Lasset C, Leroux D, Maugard C, Moretta-Serra J, Popovici C, Buecher B, Colas C, Noguès C. National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract. Eur J Med Genet 2020; 63:104080. [PMID: 33039684 DOI: 10.1016/j.ejmg.2020.104080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/29/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022]
Abstract
In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.
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Affiliation(s)
- Marion Dhooge
- APHP.Centre (Cochin Hospital), Paris University, Paris, France.
| | - Stéphanie Baert-Desurmont
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Carole Corsini
- Arnaud de Villeneuve University Hospital, Montpellier, France
| | - Olivier Caron
- Gustave-Roussy University Hospital, Villejuif, France
| | - Nadine Andrieu
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France; Unité Inserm, Institut Curie, Paris, France
| | | | | | | | - Antoine De Pauw
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | | | | | | | - Dominique Leroux
- Grenoble University Hospital, Couple-Enfant Hospital, Grenoble, France
| | | | - Jessica Moretta-Serra
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | - Cornel Popovici
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | - Bruno Buecher
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | - Chrystelle Colas
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | - Catherine Noguès
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
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28
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Djursby M, Madsen MB, Frederiksen JH, Berchtold LA, Therkildsen C, Willemoe GL, Hasselby JP, Wikman F, Okkels H, Skytte AB, Nilbert M, Wadt K, Gerdes AM, van Overeem Hansen T. New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients. Front Genet 2020; 11:566266. [PMID: 33193653 PMCID: PMC7541943 DOI: 10.3389/fgene.2020.566266] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/24/2020] [Indexed: 12/30/2022] Open
Abstract
A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.
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Affiliation(s)
- Malene Djursby
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Majbritt B Madsen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jane H Frederiksen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Lukas A Berchtold
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christina Therkildsen
- The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
| | - Gro L Willemoe
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jane P Hasselby
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Friedrik Wikman
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik Okkels
- Section of Molecular Diagnostics, Department of Clinical Chemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Anne-Bine Skytte
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Mef Nilbert
- The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
| | - Karin Wadt
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne-Marie Gerdes
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas van Overeem Hansen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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29
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Peltomäki P, Olkinuora A, Nieminen TT. Updates in the field of hereditary nonpolyposis colorectal cancer. Expert Rev Gastroenterol Hepatol 2020; 14:707-720. [PMID: 32755332 DOI: 10.1080/17474124.2020.1782187] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment. AREAS COVERED The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed. EXPERT COMMENTARY LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.
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Affiliation(s)
- Paivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
| | - Alisa Olkinuora
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
| | - Taina T Nieminen
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
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30
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May C, Ji S, Syed ZA, Revoredo L, Paul Daniel EJ, Gerken TA, Tabak LA, Samara NL, Ten Hagen KG. Differential splicing of the lectin domain of an O-glycosyltransferase modulates both peptide and glycopeptide preferences. J Biol Chem 2020; 295:12525-12536. [PMID: 32669364 DOI: 10.1074/jbc.ra120.014700] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/13/2020] [Indexed: 12/25/2022] Open
Abstract
Mucin-type O-glycosylation is an essential post-translational modification required for protein secretion, extracellular matrix formation, and organ growth. O-Glycosylation is initiated by a large family of enzymes (GALNTs in mammals and PGANTs in Drosophila) that catalyze the addition of GalNAc onto the hydroxyl groups of serines or threonines in protein substrates. These enzymes contain two functional domains: a catalytic domain and a C-terminal ricin-like lectin domain comprised of three potential GalNAc recognition repeats termed α, β, and γ. The catalytic domain is responsible for binding donor and acceptor substrates and catalyzing transfer of GalNAc, whereas the lectin domain recognizes more distant extant GalNAc on previously glycosylated substrates. We previously demonstrated a novel role for the α repeat of lectin domain in influencing charged peptide preferences. Here, we further interrogate how the differentially spliced α repeat of the PGANT9A and PGANT9B O-glycosyltransferases confers distinct preferences for a variety of endogenous substrates. Through biochemical analyses and in silico modeling using preferred substrates, we find that a combination of charged residues within the α repeat and charged residues in the flexible gating loop of the catalytic domain distinctively influence the peptide substrate preferences of each splice variant. Moreover, PGANT9A and PGANT9B also display unique glycopeptide preferences. These data illustrate how changes within the noncatalytic lectin domain can alter the recognition of both peptide and glycopeptide substrates. Overall, our results elucidate a novel mechanism for modulating substrate preferences of O-glycosyltransferases via alternative splicing within specific subregions of functional domains.
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Affiliation(s)
- Carolyn May
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland, USA
| | - Suena Ji
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland, USA
| | - Zulfeqhar A Syed
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland, USA
| | - Leslie Revoredo
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland, USA.,Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA
| | - Earnest James Paul Daniel
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA.,Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
| | - Thomas A Gerken
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA.,Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
| | - Lawrence A Tabak
- Section on Biological Chemistry, NIDCR, National Institutes of Health, Bethesda, Maryland, USA
| | - Nadine L Samara
- Structural Biochemistry Unit, NIDCR, National Institutes of Health, Bethesda, Maryland, USA
| | - Kelly G Ten Hagen
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland, USA
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31
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Schubert SA, Morreau H, de Miranda NFCC, van Wezel T. The missing heritability of familial colorectal cancer. Mutagenesis 2020; 35:221-231. [PMID: 31605533 PMCID: PMC7352099 DOI: 10.1093/mutage/gez027] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Pinpointing heritability factors is fundamental for the prevention and early detection of cancer. Up to one-quarter of colorectal cancers (CRCs) occur in the context of familial aggregation of this disease, suggesting a strong genetic component. Currently, only less than half of the heritability of CRC can be attributed to hereditary syndromes or common risk loci. Part of the missing heritability of this disease may be explained by the inheritance of elusive high-risk variants, polygenic inheritance, somatic mosaicism, as well as shared environmental factors, among others. A great deal of the missing heritability in CRC is expected to be addressed in the coming years with the increased application of cutting-edge next-generation sequencing technologies, routine multigene panel testing and tumour-focussed germline predisposition screening approaches. On the other hand, it will be important to define the contribution of environmental factors to familial aggregation of CRC incidence. This review provides an overview of the known genetic causes of familial CRC and aims at providing clues that explain the missing heritability of this disease.
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Affiliation(s)
- Stephanie A Schubert
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
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Terradas M, Capellá G, Valle L. Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes. J Clin Med 2020; 9:jcm9061954. [PMID: 32585810 PMCID: PMC7355797 DOI: 10.3390/jcm9061954] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 12/30/2022] Open
Abstract
In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene-environmental interactions, may explain the missing heritability in CRC.
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Affiliation(s)
- Mariona Terradas
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-93-260-7145
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Zilmer M, Edmondson AC, Khetarpal SA, Alesi V, Zaki MS, Rostasy K, Madsen CG, Lepri FR, Sinibaldi L, Cusmai R, Novelli A, Issa MY, Fenger CD, Abou Jamra R, Reutter H, Briuglia S, Agolini E, Hansen L, Petäjä-Repo UE, Hintze J, Raymond KM, Liedtke K, Stanley V, Musaev D, Gleeson JG, Vitali C, O’Brien WT, Gardella E, Rubboli G, Rader DJ, Schjoldager KT, Møller RS. Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function. Brain 2020; 143:1114-1126. [PMID: 32293671 PMCID: PMC7534148 DOI: 10.1093/brain/awaa063] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 12/30/2019] [Accepted: 01/20/2020] [Indexed: 11/13/2022] Open
Abstract
Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.
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Affiliation(s)
- Monica Zilmer
- Department of Paediatrics, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark
| | - Andrew C Edmondson
- Department of Pediatrics, Division of Human Genetics, Section of Biochemical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sumeet A Khetarpal
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Viola Alesi
- Medical Genetics Department, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
| | - Maha S Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt
| | - Kevin Rostasy
- Department of Paediatric Neurology, Children’s Hospital Datteln, Witten/Herdecke University, 45711 Datteln, Germany
| | - Camilla G Madsen
- Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, 2650 Hvidovre, Denmark
| | - Francesca R Lepri
- Medical Genetics Department, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
| | - Lorenzo Sinibaldi
- Medical Genetics Department, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
| | - Raffaella Cusmai
- Neurology Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
| | - Antonio Novelli
- Medical Genetics Department, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
| | - Mahmoud Y Issa
- Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt
| | - Christina D Fenger
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark
- Amplexa Genetics A/S, 5000 Odense C, Denmark
| | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig, 04103 Leipzig, Germany
| | - Heiko Reutter
- Department of Neonatology and Pediatric Intensive Care, University Hospital of Bonn, 53012 Bonn, Germany
- Institute of Human Genetics, University Hospital of Bonn, 53012 Bonn, Germany
| | | | - Emanuele Agolini
- Medical Genetics Department, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
| | - Lars Hansen
- Copenhagen Centre for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Ulla E Petäjä-Repo
- Research Unit of Biomedicine, University of Oulu, 90014 University of Oulu, Finland
| | - John Hintze
- Copenhagen Centre for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Kimiyo M Raymond
- Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | - Kristen Liedtke
- Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | - Valentina Stanley
- Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children’s Institute for Genomic Medicine, University of California, San Diego, CA 92093, USA
| | - Damir Musaev
- Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children’s Institute for Genomic Medicine, University of California, San Diego, CA 92093, USA
| | - Joseph G Gleeson
- Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children’s Institute for Genomic Medicine, University of California, San Diego, CA 92093, USA
| | - Cecilia Vitali
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - W Timothy O’Brien
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Elena Gardella
- Department of Neurophysiology, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark
| | - Guido Rubboli
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark
- Institute of Clinical Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Daniel J Rader
- Department of Pediatrics, Division of Human Genetics, Section of Biochemical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Katrine T Schjoldager
- Copenhagen Centre for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Rikke S Møller
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark
- Institute for Regional Health Services, University of Southern Denmark, 5000 Odense C, Denmark
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Lorca V, Garre P. Current status of the genetic susceptibility in attenuated adenomatous polyposis. World J Gastrointest Oncol 2019; 11:1101-1114. [PMID: 31908716 PMCID: PMC6937445 DOI: 10.4251/wjgo.v11.i12.1101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/18/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023] Open
Abstract
Adenomatous polyposis (AP) is classified according to cumulative adenoma number in classical AP (CAP) and attenuated AP (AAP). Genetic susceptibility is the major risk factor in CAP due to mutations in the known high predisposition genes APC and MUTYH. However, the contribution of genetic susceptibility to AAP is lower and less understood. New predisposition genes have been recently proposed, and some of them have been validated, but their scarcity hinders accurate risk estimations and prevalence calculations. AAP is a heterogeneous condition in terms of severity, clinical features and heritability. Therefore, clinicians do not have strong discriminating criteria for the recommendation of the genetic study of known predisposition genes, and the detection rate is low. Elucidation and knowledge of new AAP high predisposition genes are of great importance to offer accurate genetic counseling to the patient and family members. This review aims to update the genetic knowledge of AAP, and to expound the difficulties involved in the genetic analysis of a highly heterogeneous condition such as AAP.
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Affiliation(s)
- Víctor Lorca
- Laboratorio de Oncología Molecular, Grupo de Investigación Clínica y Traslacional en Oncología, Hospital Clínico San Carlos, Madrid 28040, Spain
| | - Pilar Garre
- Laboratorio de Oncología Molecular, Servicio de Oncología, Hospital Clínico San Carlos, Madrid 28040, Spain
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He Y, Schreiber K, Wolf SP, Wen F, Steentoft C, Zerweck J, Steiner M, Sharma P, Shepard HM, Posey A, June CH, Mandel U, Clausen H, Leisegang M, Meredith SC, Kranz DM, Schreiber H. Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell. JCI Insight 2019; 4:130416. [PMID: 31672936 PMCID: PMC6948763 DOI: 10.1172/jci.insight.130416] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 09/11/2019] [Indexed: 12/22/2022] Open
Abstract
Human cancer cells were eradicated by adoptive transfer of T cells transduced with a chimeric antigen receptor (CAR) made from an antibody (237Ab) that is highly specific for the murine Tn-glycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CAR-transduced T (CART) cells and the mechanism for the absence of relapse. We show that although the 237Ab bound only to cell lines expressing murine Tn-PDPN, the 237Ab-derived 237CART cells lysed multiple different human and murine cancers not predicted by the 237Ab binding. Nevertheless, the 237CART cell reactivities remained cancer specific because all recognitions were dependent on the Tn glycosylation that resulted from COSMC mutations that were not present in normal tissues. While Tn was required for the recognition by 237CART, Tn alone was not sufficient for 237CART cell activation. Activation of 237CART cells required peptide backbone recognition but tolerated substitutions of up to 5 of the 7 amino acid residues in the motif recognized by 237Ab. Together, these findings demonstrate what we believe is a new principle whereby simultaneous recognition of multiple independent Tn-glycopeptide antigens on a cancer cell makes tumor escape due to antigen loss unlikely.
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Affiliation(s)
| | - Karin Schreiber
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Steven P. Wolf
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Frank Wen
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Catharina Steentoft
- Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Jonathan Zerweck
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Madeline Steiner
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Preeti Sharma
- Department of Biochemistry, University of Illinois, Urbana, Illinois, USA
| | | | - Avery Posey
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Center for Cellular Therapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Carl H. June
- Center for Cellular Therapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ulla Mandel
- Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Clausen
- Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Matthias Leisegang
- Institute of Immunology, Charité - Universitätsmedizin Berlin, Campus Buch, Berlin, Germany
| | | | - David M. Kranz
- Department of Biochemistry, University of Illinois, Urbana, Illinois, USA
| | - Hans Schreiber
- Committee on Cancer Biology, and
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
- Committee on Immunology, The University of Chicago, Chicago, Illinois, USA
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Fernandez AJ, Daniel EJP, Mahajan SP, Gray JJ, Gerken TA, Tabak LA, Samara NL. The structure of the colorectal cancer-associated enzyme GalNAc-T12 reveals how nonconserved residues dictate its function. Proc Natl Acad Sci U S A 2019; 116:20404-20410. [PMID: 31548401 PMCID: PMC6789641 DOI: 10.1073/pnas.1902211116] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Polypeptide N-acetylgalactosaminyl transferases (GalNAc-Ts) initiate mucin type O-glycosylation by catalyzing the transfer of N-acetylgalactosamine (GalNAc) to Ser or Thr on a protein substrate. Inactive and partially active variants of the isoenzyme GalNAc-T12 are present in subsets of patients with colorectal cancer, and several of these variants alter nonconserved residues with unknown functions. While previous biochemical studies have demonstrated that GalNAc-T12 selects for peptide and glycopeptide substrates through unique interactions with its catalytic and lectin domains, the molecular basis for this distinct substrate selectivity remains elusive. Here we examine the molecular basis of the activity and substrate selectivity of GalNAc-T12. The X-ray crystal structure of GalNAc-T12 in complex with a di-glycosylated peptide substrate reveals how a nonconserved GalNAc binding pocket in the GalNAc-T12 catalytic domain dictates its unique substrate selectivity. In addition, the structure provides insight into how colorectal cancer mutations disrupt the activity of GalNAc-T12 and illustrates how the rules dictating GalNAc-T12 function are distinct from those for other GalNAc-Ts.
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Affiliation(s)
- Amy J Fernandez
- Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
| | | | - Sai Pooja Mahajan
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218
| | - Jeffrey J Gray
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218
- Program in Molecular Biophysics, The Johns Hopkins University, Baltimore, MD 21218
| | - Thomas A Gerken
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106
- Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106
| | - Lawrence A Tabak
- Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
| | - Nadine L Samara
- Structural Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892
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Bonjoch L, Mur P, Arnau-Collell C, Vargas-Parra G, Shamloo B, Franch-Expósito S, Pineda M, Capellà G, Erman B, Castellví-Bel S. Approaches to functionally validate candidate genetic variants involved in colorectal cancer predisposition. Mol Aspects Med 2019; 69:27-40. [PMID: 30935834 DOI: 10.1016/j.mam.2019.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/26/2019] [Accepted: 03/26/2019] [Indexed: 02/07/2023]
Abstract
Most next generation sequencing (NGS) studies identified candidate genetic variants predisposing to colorectal cancer (CRC) but do not tackle its functional interpretation to unequivocally recognize a new hereditary CRC gene. Besides, germline variants in already established hereditary CRC-predisposing genes or somatic variants share the same need when trying to categorize those with relevant significance. Functional genomics approaches have an important role in identifying the causal links between genetic architecture and phenotypes, in order to decipher cellular function in health and disease. Therefore, functional interpretation of identified genetic variants by NGS platforms is now essential. Available approaches nowadays include bioinformatics, cell and molecular biology and animal models. Recent advances, such as the CRISPR-Cas9, ZFN and TALEN systems, have been already used as a powerful tool with this objective. However, the use of cell lines is of limited value due to the CRC heterogeneity and its close interaction with microenvironment. Access to tridimensional cultures or organoids and xenograft models that mimic the in vivo tissue architecture could revolutionize functional analysis. This review will focus on the application of state-of-the-art functional studies to better tackle new genes involved in germline predisposition to this neoplasm.
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Affiliation(s)
- Laia Bonjoch
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Pilar Mur
- Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Coral Arnau-Collell
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Gardenia Vargas-Parra
- Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Bahar Shamloo
- Molecular Biology, Genetics, and Bioengineering Department, Legacy Research Institute, Portland, OR, USA
| | - Sebastià Franch-Expósito
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Marta Pineda
- Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Gabriel Capellà
- Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Batu Erman
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
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Valle L, de Voer RM, Goldberg Y, Sjursen W, Försti A, Ruiz-Ponte C, Caldés T, Garré P, Olsen MF, Nordling M, Castellvi-Bel S, Hemminki K. Update on genetic predisposition to colorectal cancer and polyposis. Mol Aspects Med 2019; 69:10-26. [PMID: 30862463 DOI: 10.1016/j.mam.2019.03.001] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/26/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
Abstract
The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.
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Affiliation(s)
- Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.
| | - Richarda M de Voer
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Yael Goldberg
- Raphael Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - Wenche Sjursen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Medical Genetics, St Olavs University Hospital, Trondheim, Norway
| | - Asta Försti
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany
| | - Clara Ruiz-Ponte
- Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain
| | - Trinidad Caldés
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain; Oncology Molecular Laboratory, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - Pilar Garré
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain; Oncology Molecular Laboratory, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - Maren F Olsen
- Department of Medical Genetics, St Olavs University Hospital, Trondheim, Norway
| | - Margareta Nordling
- Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sergi Castellvi-Bel
- Genetic Predisposition to Gastrointestinal Cancer Group, Gastrointestinal and Pancreatic Oncology Team, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
| | - Kari Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.
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Mao Y, Zhang Y, Fan S, Chen L, Tang L, Chen X, Lyu J. GALNT6 Promotes Tumorigenicity and Metastasis of Breast Cancer Cell via β-catenin/MUC1-C Signaling Pathway. Int J Biol Sci 2019; 15:169-182. [PMID: 30662357 PMCID: PMC6329923 DOI: 10.7150/ijbs.29048] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/02/2018] [Indexed: 01/07/2023] Open
Abstract
Polypeptide N-acetylgalactosaminyl transferase-6 (GALNT6), a member of the N-acetyl-D-galactosamine transferase family, was shown to be over-expression in mammary cancer and could be used as a biomarker. However, its roles and underlying mechanisms in the pathogenesis of breast cancer are still unclear. In this study, we reported that GALNT6 was up-expression in breast cancer, and it was not associated with tumor stage. The expression level of GALNT6 and menopause status was associated with patient survival. Biological function results illustrated that knockdown of GALNT6 inhibited proliferation, migration and invasion of MDA-MB-231 cells, and increased cell apoptosis. Knockdown of GALNT6 in breast cancer cell attenuated the protein expression of PCNA, cyclin D1, C-myc and β-catenin, and increased the expression of E-cadherin, caspase 3 and cleaved PARP1. Cell fractionation assay showed that knockdown of GALNT6 reduced the levels of β-catenin and MUC1-C in nucleus. Simultaneously knockdown of GALNT6 and β-catenin significantly reduced the level of C-myc. Co-IP experiments indicated that GALNT6 interacted with MUC1-N, β-catenin interacting with MUC1-C in breast cancer cells. Together, our study reveals that GALNT6 promotes tumorigenicity and metastasis through β-catenin/MUC1-C signaling pathway.
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Affiliation(s)
- Yingge Mao
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Present address: The First Affiliated Hospital of Henan University
| | - Yuqi Zhang
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Sairong Fan
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lvao Chen
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lili Tang
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoming Chen
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianxin Lyu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Hangzhou Medical College, Hangzhou, Zhejiang, China
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Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, Conti DV, Qu C, Jeon J, Edlund CK, Greenside P, Wainberg M, Schumacher FR, Smith JD, Levine DM, Nelson SC, Sinnott-Armstrong NA, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Bamia C, Banbury BL, Baron JA, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Chirlaque MD, Cho SH, Connolly CM, Cross AJ, Cuk K, Curtis KR, de la Chapelle A, Doheny KF, Duggan D, Easton DF, Elias SG, Elliott F, English DR, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Forman D, Gala M, Gallinger S, Gauderman WJ, Giles GG, Gillanders E, Gong J, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hampel H, Harlid S, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Hunter DJ, Ibañez-Sanz G, Idos GE, Ingersoll R, Jackson RD, Jacobs EJ, Jenkins MA, Joshi AD, Joshu CE, Keku TO, Key TJ, Kim HR, Kobayashi E, Kolonel LN, Kooperberg C, Kühn T, Küry S, et alHuyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, Conti DV, Qu C, Jeon J, Edlund CK, Greenside P, Wainberg M, Schumacher FR, Smith JD, Levine DM, Nelson SC, Sinnott-Armstrong NA, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Bamia C, Banbury BL, Baron JA, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Chirlaque MD, Cho SH, Connolly CM, Cross AJ, Cuk K, Curtis KR, de la Chapelle A, Doheny KF, Duggan D, Easton DF, Elias SG, Elliott F, English DR, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Forman D, Gala M, Gallinger S, Gauderman WJ, Giles GG, Gillanders E, Gong J, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hampel H, Harlid S, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Hunter DJ, Ibañez-Sanz G, Idos GE, Ingersoll R, Jackson RD, Jacobs EJ, Jenkins MA, Joshi AD, Joshu CE, Keku TO, Key TJ, Kim HR, Kobayashi E, Kolonel LN, Kooperberg C, Kühn T, Küry S, Kweon SS, Larsson SC, Laurie CA, Le Marchand L, Leal SM, Lee SC, Lejbkowicz F, Lemire M, Li CI, Li L, Lieb W, Lin Y, Lindblom A, Lindor NM, Ling H, Louie TL, Männistö S, Markowitz SD, Martín V, Masala G, McNeil CE, Melas M, Milne RL, Moreno L, Murphy N, Myte R, Naccarati A, Newcomb PA, Offit K, Ogino S, Onland-Moret NC, Pardini B, Parfrey PS, Pearlman R, Perduca V, Pharoah PDP, Pinchev M, Platz EA, Prentice RL, Pugh E, Raskin L, Rennert G, Rennert HS, Riboli E, Rodríguez-Barranco M, Romm J, Sakoda LC, Schafmayer C, Schoen RE, Seminara D, Shah M, Shelford T, Shin MH, Shulman K, Sieri S, Slattery ML, Southey MC, Stadler ZK, Stegmaier C, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Thomas SS, Toland AE, Trichopoulou A, Ulrich CM, Van Den Berg DJ, van Duijnhoven FJB, Van Guelpen B, van Kranen H, Vijai J, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Win AK, Wolf CR, Wolk A, Woods MO, Wu AH, Zaidi SH, Zanke BW, Zhang Q, Zheng W, Scacheri PC, Potter JD, Bassik MC, Kundaje A, Casey G, Moreno V, Abecasis GR, Nickerson DA, Gruber SB, Hsu L, Peters U. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet 2019; 51:76-87. [PMID: 30510241 PMCID: PMC6358437 DOI: 10.1038/s41588-018-0286-6] [Show More Authors] [Citation(s) in RCA: 376] [Impact Index Per Article: 62.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 10/22/2018] [Indexed: 12/17/2022]
Abstract
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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Affiliation(s)
- Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephanie A Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hyun Min Kang
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Sai Chen
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Stephanie L Schmit
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - David V Conti
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jihyoun Jeon
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
| | - Christopher K Edlund
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Peyton Greenside
- Biomedical Informatics Program, Stanford University, Stanford, CA, USA
| | - Michael Wainberg
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | - Fredrick R Schumacher
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Joshua D Smith
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - David M Levine
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Sarah C Nelson
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | | | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - M Henar Alonso
- Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Kristin Anderson
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - Coral Arnau-Collell
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christina Bamia
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - John A Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - D Timothy Bishop
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Juergen Boehm
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefanie Brezina
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Stephan Buch
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | | | - Katja Butterbach
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bette J Caan
- Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Christopher S Carlson
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Maria-Dolores Chirlaque
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain
| | - Sang Hee Cho
- Department of Hematology-Oncology, Chonnam National University Hospital, Hwasun, South Korea
| | - Charles M Connolly
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Katarina Cuk
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Keith R Curtis
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kimberly F Doheny
- Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - David Duggan
- Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ, USA
| | - Douglas F Easton
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Sjoerd G Elias
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Faye Elliott
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Dallas R English
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Edith J M Feskens
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Rocky Fischer
- University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA
| | - Liesel M FitzGerald
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - David Forman
- International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Manish Gala
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - W James Gauderman
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Elizabeth Gillanders
- Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA
| | - Jian Gong
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - John S Grove
- University of Hawaii Cancer Research Center, Honolulu, HI, USA
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Robert W Haile
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Richard B Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA
| | - Philipp Hofer
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea
| | - Wan-Ling Hsu
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Thomas J Hudson
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - David J Hunter
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Gemma Ibañez-Sanz
- Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Gastroenterology Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Gregory E Idos
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Roxann Ingersoll
- Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Rebecca D Jackson
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA
| | - Eric J Jacobs
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Amit D Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Corinne E Joshu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Timothy J Key
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Hyeong Rok Kim
- Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea
| | - Emiko Kobayashi
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Laurence N Kolonel
- Office of Public Health Studies, University of Hawaii Manoa, Honolulu, HI, USA
| | - Charles Kooperberg
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sébastien Küry
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Cecelia A Laurie
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | | | - Suzanne M Leal
- Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Soo Chin Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Flavio Lejbkowicz
- The Clalit Health Services, Personalized Genomic Service, Carmel, Haifa, Israel
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Mathieu Lemire
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Li Li
- Center for Community Health Integration and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Wolfgang Lieb
- Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Noralane M Lindor
- Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Hua Ling
- Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Tin L Louie
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Satu Männistö
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland
| | - Sanford D Markowitz
- Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH, USA
| | - Vicente Martín
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Biomedicine Institute (IBIOMED), University of León, León, Spain
| | - Giovanna Masala
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute of Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy
| | - Caroline E McNeil
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Marilena Melas
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Roger L Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Lorena Moreno
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Neil Murphy
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Robin Myte
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Alessio Naccarati
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Shuji Ogino
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - N Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Barbara Pardini
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Patrick S Parfrey
- The Clinical Epidemiology Unit, Memorial University Medical School, Newfoundland, Canada
| | - Rachel Pearlman
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Vittorio Perduca
- Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France
- CESP (Inserm U1018), Facultés de Medicine Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif, France
| | - Paul D P Pharoah
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Mila Pinchev
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Ross L Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Elizabeth Pugh
- Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Leon Raskin
- Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Hedy S Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Elio Riboli
- School of Public Health, Imperial College London, London, UK
| | - Miguel Rodríguez-Barranco
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain
| | - Jane Romm
- Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Clemens Schafmayer
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Daniela Seminara
- Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA
| | - Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Tameka Shelford
- Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Min-Ho Shin
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea
| | | | - Sabina Sieri
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Melissa C Southey
- Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Yu-Ru Su
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Catherine M Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Duncan C Thomas
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Sushma S Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Amanda E Toland
- Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - David J Van Den Berg
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Henk van Kranen
- National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Joseph Vijai
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Korbinian Weigl
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Aung Ko Win
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - C Roland Wolf
- School of Medicine, University of Dundee, Dundee, Scotland, UK
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Michael O Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada
| | - Anna H Wu
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Syed H Zaidi
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Brent W Zanke
- Division of Hematology, University of Toronto, Toronto, Ontario, Canada
| | - Qing Zhang
- Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Peter C Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | - Anshul Kundaje
- Department of Computer Science, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Victor Moreno
- Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Goncalo R Abecasis
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | | | - Stephen B Gruber
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Department of Epidemiology, University of Washington, Seattle, WA, USA.
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Cragun DL, Kechik J, Pal T. Complexities of genetic screening and testing in hereditary colorectal cancer. SEMINARS IN COLON AND RECTAL SURGERY 2018. [DOI: 10.1053/j.scrs.2018.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Ji S, Samara NL, Revoredo L, Zhang L, Tran DT, Muirhead K, Tabak LA, Ten Hagen KG. A molecular switch orchestrates enzyme specificity and secretory granule morphology. Nat Commun 2018; 9:3508. [PMID: 30158631 PMCID: PMC6115407 DOI: 10.1038/s41467-018-05978-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 08/01/2018] [Indexed: 12/22/2022] Open
Abstract
Regulated secretion is an essential process where molecules destined for export are directed to membranous secretory granules, where they undergo packaging and maturation. Here, we identify a gene (pgant9) that influences the structure and shape of secretory granules within the Drosophila salivary gland. Loss of pgant9, which encodes an O-glycosyltransferase, results in secretory granules with an irregular, shard-like morphology, and altered glycosylation of cargo. Interestingly, pgant9 undergoes a splicing event that acts as a molecular switch to alter the charge of a loop controlling access to the active site of the enzyme. The splice variant with the negatively charged loop glycosylates the positively charged secretory cargo and rescues secretory granule morphology. Our study highlights a mechanism for dictating substrate specificity within the O-glycosyltransferase enzyme family. Moreover, our in vitro and in vivo studies suggest that the glycosylation status of secretory cargo influences the morphology of maturing secretory granules.
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Affiliation(s)
- Suena Ji
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Nadine L Samara
- Section on Biological Chemistry, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Leslie Revoredo
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Liping Zhang
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Duy T Tran
- Section on Biological Chemistry, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Kayla Muirhead
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Lawrence A Tabak
- Section on Biological Chemistry, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA
| | - Kelly G Ten Hagen
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD, 20892-4370, USA.
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Yan X, Lu J, Zou X, Zhang S, Cui Y, Zhou L, Liu F, Shan A, Lu J, Zheng M, Feng B, Zhang Y. The polypeptide N-acetylgalactosaminyltransferase 4 exhibits stage-dependent expression in colorectal cancer and affects tumorigenesis, invasion and differentiation. FEBS J 2018; 285:3041-3055. [PMID: 29931806 DOI: 10.1111/febs.14593] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 05/20/2018] [Accepted: 06/20/2018] [Indexed: 12/18/2022]
Abstract
The aberrant expression of mucin-type O-glycosylation plays important roles in cancer malignancy. The polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) are a family of conserved enzymes that initiate the mucin-type O-glycosylation in cells. In human, consistent up- or down-regulation of ppGalNAc-Ts expression during cancer development has been frequently reported. Here, we provide evidence that ppGalNAc-T4 shows a stage-dependent expression at the different stages of colorectal cancer (CRC) in the 62 pair-matched tumor/normal tissues. In detail, ppGalNAc-T4 expression is significantly induced at stage I and II but not at stage III and IV. Overexpression of ppGalNAc-T4 in CRC cells enhances colony formation and sphere formation suggesting an important role of ppGalNAc-T4 in tumorigenesis. Conversely, knockdown of ppGalNAc-T4 in CRC cells increases the cell migration and invasion, and leads to an epithelial-mesenchymal transition-like transition. Further analysis suggests that loss of ppGalNAc-T4 contributes to the dedifferentiation of CRC and high expression of ppGalNAc-T4 correlates to a good prognosis of patients. Taken together, our results not only demonstrate a stage-dependent expression of ppGalNAc-T4 in CRC progression, but also suggest that such stage-dependent expression may contribute to the tumorigenesis at the early stage and promote cell migration and invasion at the advanced stage.
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Affiliation(s)
- Xialin Yan
- Department of General Surgery, Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Jishun Lu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Xia Zou
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Sen Zhang
- Department of General Surgery, Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Yalu Cui
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Leqi Zhou
- Department of General Surgery, Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Feng Liu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Aidong Shan
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
| | - Jiaoyang Lu
- Department of General Surgery, Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Minghua Zheng
- Department of General Surgery, Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Bo Feng
- Department of General Surgery, Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Yan Zhang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, China
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Li Y, Zeng C, Hu J, Pan Y, Shan Y, Liu B, Jia L. Long non-coding RNA-SNHG7 acts as a target of miR-34a to increase GALNT7 level and regulate PI3K/Akt/mTOR pathway in colorectal cancer progression. J Hematol Oncol 2018; 11:89. [PMID: 29970122 PMCID: PMC6029165 DOI: 10.1186/s13045-018-0632-2] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 06/22/2018] [Indexed: 12/18/2022] Open
Abstract
Background Colorectal cancer (CRC) arises in a multistep molecular network process, which is from either discrete genetic perturbation or epigenetic dysregulation. The long non-coding RNAs (lncRNAs), emerging as key molecules in human malignancy, has become one of the hot topics in RNA biology. Aberrant O-glycosylation is a well-described hallmark of many cancers. GALNT7 acts as a glycosyltransferase in protein O-glycosylation, involving in the occurrence and development of CRC. Methods The microarrays were used to survey the lncRNA and mRNA expression profiles of primary CRC cell line SW480 and metastatic CRC cell line SW620. Cell proliferation, migration, invasion, and apoptosis were assayed. Xenograft mouse models were used to determine the role of lncRNA-SNHG7 in CRC in vivo. In addition, CNC analysis and competing endogenous analysis were used to detect differential SNHG7 and relational miRNAs expression in CRC cell lines. Results SNHG7 expression showed a high fold (SW620/SW480) in CRC microarrays. The CRC patients with high expression of SNHG7 had a significantly poor prognosis. Furthermore, SNHG7 promoted CRC cell proliferation, metastasis, mediated cell cycle, and inhibited apoptosis. SNHG7 and GALNT7 were observed for co-expression by CNC analysis, and a negative correlation of SNHG7 and miR-34a were found by competing endogenous RNA (ceRNA) analysis. Further results indicated that SNHG7 facilitated the proliferation and metastasis as a competing endogenous RNA to regulate GALNT7 expression by sponging miR-34a in CRC cell lines. SNHG7 also played the oncogenic role in regulating PI3K/Akt/mTOR pathway by competing endogenous miR-34a and GALNT7. Conclusion The CRC-related SNHG7 and miR-34a might be implicated in CRC progression via GALNT7, suggesting the potential usage of SNHG7/miR-34a/GALNT7 axis in CRC treatment. Electronic supplementary material The online version of this article (10.1186/s13045-018-0632-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yang Li
- College of Laboratory Medicine, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Changqian Zeng
- Medical College, Dalian University, Dalian, 116622, Liaoning Province, China
| | - Jialei Hu
- College of Laboratory Medicine, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Yue Pan
- College of Laboratory Medicine, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Yujia Shan
- College of Laboratory Medicine, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Bing Liu
- College of Laboratory Medicine, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Li Jia
- College of Laboratory Medicine, Dalian Medical University, Dalian, 116044, Liaoning Province, China.
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45
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Sahasrabudhe NM, Lenos K, van der Horst JC, Rodríguez E, van Vliet SJ. Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3. Biol Chem 2018; 399:649-659. [PMID: 29894293 DOI: 10.1515/hsz-2018-0120] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/12/2018] [Indexed: 01/06/2023]
Abstract
Colorectal cancer is the third most common cancer type worldwide. It is characterized by a high expression of aberrantly glycosylated ligands, such as the Tn antigen (GalNAcα1-Ser/Thr), which is a major ligand for the C-type lectin macrophage galactose-type lectin (MGL). We have previously determined that a high level of MGL ligands in colorectal tumors is associated with lower disease-free survival in patients with late stage disease, which we could attribute to the presence of oncogenic BRAFV600E mutations. Here we aimed to elucidate the downstream pathway of BRAFV600E governing high MGL ligand and Tn antigen expression. We focused on glycosylation-related enzymes involved in the synthesis or elongation of Tn antigen, N-acetylgalactosamine-transferases (GALNTs) and C1GalT1/COSMC, respectively. Both the activity and expression of C1GalT1 and COSMC were unrelated to the BRAF mutational status. In contrast, GALNT3, GALNT7 and GALNT12 were increased in colorectal cancer cells harboring the BRAFV600E mutation. Through CRISPR-Cas9 gene knockouts we could establish that GALNT3 increased MGL ligand synthesis in the HT29 cell line, while GALNT7 and GALNT12 appeared to have redundant roles. Together our results highlight a novel mechanistic pathway connecting BRAFV600E to aberrant glycosylation in colorectal cancer through GALNT3.
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Affiliation(s)
- Neha M Sahasrabudhe
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Kristiaan Lenos
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Joost C van der Horst
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Ernesto Rodríguez
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Sandra J van Vliet
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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Evans DR, Venkitachalam S, Revoredo L, Dohey AT, Clarke E, Pennell JJ, Powell AE, Quinn E, Ravi L, Gerken TA, Green JS, Woods MO, Guda K. Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer. Hum Mutat 2018; 39:1092-1101. [PMID: 29749045 DOI: 10.1002/humu.23549] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 05/05/2018] [Accepted: 05/07/2018] [Indexed: 12/29/2022]
Abstract
Characterizing moderate penetrance susceptibility genes is an emerging frontier in colorectal cancer (CRC) research. GALNT12 is a strong candidate CRC-susceptibility gene given previous linkage and association studies, and inactivating somatic and germline alleles in CRC patients. Previously, we found rare segregating germline GALNT12 variants in a clinic-based cohort (N = 118) with predisposition for CRC. Here, we screened a new population-based cohort of incident CRC cases (N = 479) for rare (MAF ≤1%) deleterious germline GALNT12 variants. GALNT12 screening revealed eight rare variants. Two variants were previously described (p.Asp303Asn, p.Arg297Trp), and additionally, we found six other rare variants: five missense (p.His101Gln, p.Ile142Thr, p.Glu239Gln, p.Thr286Met, p.Val290Phe) and one putative splice-altering variant (c.732-8 G>T). Sequencing of population-matched controls (N = 400) revealed higher burden of these variants in CRC cases compared with healthy controls (P = 0.0381). We then functionally characterized the impact of substitutions on GALNT12 enzyme activity using in vitro-derived peptide substrates. Three of the newly identified GALNT12 missense variants (p.His101Gln, p.Ile142Thr, p.Val290Phe) demonstrated a marked loss (>2-fold reduction) of enzymatic activity compared with wild-type (P ≤ 0.05), whereas p.Glu239Gln exhibited a ∼2-fold reduction in activity (P = 0.077). These findings provide strong, independent evidence for the association of GALNT12 defects with CRC-susceptibility; underscoring implications for glycosylation pathway defects in CRC.
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Affiliation(s)
- Daniel R Evans
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Srividya Venkitachalam
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Leslie Revoredo
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio
| | - Amanda T Dohey
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Erica Clarke
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Julia J Pennell
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Amy E Powell
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Erina Quinn
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Lakshmeswari Ravi
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Thomas A Gerken
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio.,Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio.,Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Jane S Green
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Michael O Woods
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada
| | - Kishore Guda
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
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Ubillos L, Berriel E, Mazal D, Victoria S, Barrios E, Osinaga E, Berois N. Polypeptide-GalNAc-T6 expression predicts better overall survival in patients with colon cancer. Oncol Lett 2018; 16:225-234. [PMID: 29928405 PMCID: PMC6006374 DOI: 10.3892/ol.2018.8686] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 04/23/2018] [Indexed: 12/22/2022] Open
Abstract
Colorectal carcinoma (CRC) is the second leading cause of cancer mortality worldwide. O-glycosylated mucins at the cell surface of colonic mucosa exhibit alterations in cancer and are involved in fundamental biological processes, including invasion and metastasis. Certain members of the GalNAc-transferase family may be responsible for these changes and are being investigated as novel biomarkers of cancer. In the present study the prognostic significance of GalNAc-T6 was investigated in patients with CRC patients. GalNAc-T6 expression was observed in all three colon cancer cell lines analyzed by reverse transcription-polymerase chain reaction, immunofluorescence and flow cytometry. A cohort of 81 colon cancer specimens was analyzed by immunohistochemical staining using MAb T6.3. It was demonstrated that GalNAc-T6 was expressed in 35/81 (43%) cases of colon cancer but not in the normal colonic mucosa. No association was observed with the clinical-pathologic parameters. However, patients expressing GalNAc-T6 had a significantly increased overall survival (median, 58 months; P<0.001) compared with GalNAc-T6 negative patients, especially those with advanced disease. These results suggest that GalNAc-T6 expression predicts an improved outcome in patients with CRC. The molecular mechanism underlying the less aggressive behavior of colon cancer cells expressing GalNAc-T6 remains to be elucidated.
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Affiliation(s)
- Luis Ubillos
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay.,Servicio de Oncología Clínica, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Edgardo Berriel
- Clínica Quirúrgica 1, Hospital Pasteur, Facultad de Medicina, Universidad de la República, Montevideo 11400, Uruguay.,Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Daniel Mazal
- Cátedra de Anatomía Patológica, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Sabina Victoria
- Unidad de Biología Celular, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Enrique Barrios
- Departamento de Métodos Cuantitativos, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Eduardo Osinaga
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay.,Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Nora Berois
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
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48
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Jiao X, Liu W, Mahdessian H, Bryant P, Ringdahl J, Timofeeva M, Farrington SM, Dunlop M, Lindblom A. Recurrent, low-frequency coding variants contributing to colorectal cancer in the Swedish population. PLoS One 2018; 13:e0193547. [PMID: 29547645 PMCID: PMC5856271 DOI: 10.1371/journal.pone.0193547] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 02/13/2018] [Indexed: 12/20/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified dozens of common genetic variants associated with risk of colorectal cancer (CRC). However, the majority of CRC heritability remains unclear. In order to discover low-frequency, high-risk CRC susceptibility variants in Swedish population, we genotyped 1 515 CRC patients enriched for familial cases, and 12 108 controls. Case/control association analysis suggested eight novel variants associated with CRC risk (OR 2.0-17.6, p-value < 2.0E-07), comprised of seven coding variants in genes RAB11FIP5, POTEA, COL27A1, MUC5B, PSMA8, MYH7B, and PABPC1L as well as one variant downstream of NEU1 gene. We also confirmed 27 out of 30 risk variants previously reported from GWAS in CRC with a mixed European population background. This study identified rare, coding sequence variants associated with CRC risk through analysis in a relatively homogeneous population. The segregation data suggest a complex mode of inheritance in seemingly dominant pedigrees.
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Affiliation(s)
- Xiang Jiao
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Wen Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Hovsep Mahdessian
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Patrick Bryant
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Jenny Ringdahl
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
- MRC Human Genetics Unit, Western General Hospital Edinburgh, Edinburgh, United Kingdom
| | - Susan M. Farrington
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
- MRC Human Genetics Unit, Western General Hospital Edinburgh, Edinburgh, United Kingdom
| | - Malcolm Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
- MRC Human Genetics Unit, Western General Hospital Edinburgh, Edinburgh, United Kingdom
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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49
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Thutkawkorapin J, Mahdessian H, Barber T, Picelli S, von Holst S, Lundin J, Valle L, Kontham V, Liu T, Nilsson D, Jiao X, Lindblom A. Two novel colorectal cancer risk loci in the region on chromosome 9q22.32. Oncotarget 2018. [PMID: 29541405 PMCID: PMC5834248 DOI: 10.18632/oncotarget.24340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782). Two overlapping haplotypes were suggested. One 10-SNP haplotype was indicated in familial CRC (OR 1.4, p = 0.00005) and one 25-SNP haplotype was indicated in sporadic CRC (OR 2.2, p = 0.0000012). The allele frequencies of the 10-SNP and the 25-SNP haplotypes were 13.7% and 2.5% respectively and both included one RNA, RP11-332M4.1 and RP11-l80l4.2, in the non-overlapping regions. The sporadic 25-SNP haplotype could not be studied further, but the familial 10-SNP haplotype was analyzed in 61 additional CRC families, and 6 of them were informative for all markers and had the risk haplotype. Targeted sequencing of the 10-SNP region in the linked families identified one variant in RP11-332M4.1, suggestive to confer the increased CRC risk on this haplotype. Our results support the presence of two loci at 9q22.32, each with one RNA as the putative cause of increased CRC risk. These RNAs could exert their effect through the same, or different, genes/pathways, possibly through the regulation of neighboring genes, such as PTCH1, FANCC, DKFZP434H0512, ERCC6L2 or the processed transcript LINC00046.
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Affiliation(s)
- Jessada Thutkawkorapin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Hovsep Mahdessian
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Tom Barber
- The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
| | - Simone Picelli
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Susanna von Holst
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Johanna Lundin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Barcelona 08908, Spain
| | - Vinaykumar Kontham
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Tao Liu
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Xiang Jiao
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
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50
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Hussain MRM, Hoessli DC, Fang M. N-acetylgalactosaminyltransferases in cancer. Oncotarget 2018; 7:54067-54081. [PMID: 27322213 PMCID: PMC5288242 DOI: 10.18632/oncotarget.10042] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/30/2016] [Indexed: 12/11/2022] Open
Abstract
Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNTs) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.
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Affiliation(s)
- Muhammad Ramzan Manwar Hussain
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Daniel C Hoessli
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Min Fang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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