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Wang W, Okajima T, Takeuchi H. Significant Roles of Notch O-Glycosylation in Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27061783. [PMID: 35335147 PMCID: PMC8950332 DOI: 10.3390/molecules27061783] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 12/27/2022]
Abstract
Notch signaling, which was initially identified in Drosophila wing morphogenesis, plays pivotal roles in cell development and differentiation. Optimal Notch pathway activity is essential for normal development and dysregulation of Notch signaling leads to various human diseases, including many types of cancers. In hematopoietic cancers, such as T-cell acute lymphoblastic leukemia, Notch plays an oncogenic role, while in acute myeloid leukemia, it has a tumor-suppressive role. In solid tumors, such as hepatocellular carcinoma and medulloblastoma, Notch may have either an oncogenic or tumor-suppressive role, depending on the context. Aberrant expression of Notch receptors or ligands can alter the ligand-dependent Notch signaling and changes in trafficking can lead to ligand-independent signaling. Defects in any of the two signaling pathways can lead to tumorigenesis and tumor progression. Strikingly, O-glycosylation is one such process that modulates ligand–receptor binding and trafficking. Three types of O-linked modifications on the extracellular epidermal growth factor-like (EGF) repeats of Notch receptors are observed, namely O-glucosylation, O-fucosylation, and O-N-acetylglucosamine (GlcNAc) modifications. In addition, O-GalNAc mucin-type O-glycosylation outside the EGF repeats also appears to occur in Notch receptors. In this review, we first briefly summarize the basics of Notch signaling, describe the latest information on O-glycosylation of Notch receptors classified on a structural basis, and finally describe the regulation of Notch signaling by O-glycosylation in cancer.
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Affiliation(s)
- Weiwei Wang
- Department of Molecular Biochemistry, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan; (W.W.); (T.O.)
| | - Tetsuya Okajima
- Department of Molecular Biochemistry, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan; (W.W.); (T.O.)
- Institute for Glyco-Core Research (iGCORE), Integrated Glyco-Biomedical Research Center, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Hideyuki Takeuchi
- Department of Molecular Biochemistry, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan; (W.W.); (T.O.)
- Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
- Correspondence:
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Liu W, Gou H, Wang X, Li X, Hu X, Su H, Li S, Yu J. TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling. Oncogene 2021; 40:6666-6679. [PMID: 34642500 PMCID: PMC8660633 DOI: 10.1038/s41388-021-01838-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/02/2021] [Accepted: 05/10/2021] [Indexed: 12/23/2022]
Abstract
Copy number alterations are crucial for gastric cancer (GC) development. In this study, Tocopherol alpha transfer protein-like (TTPAL) was identified to be highly amplified in our primary GC cohort (30/86). Multivariate analysis showed that high TTPAL expression was correlated with the poor prognosis of GC patients. Ectopic expression of TTPAL promoted GC cell proliferation, migration, and invasion in vitro and promoted murine xenograft tumor growth and lung metastasis in vivo. Conversely, silencing of TTPAL exerted significantly opposite effects in vitro. Moreover, RNA-sequencing and co-immunoprecipitation (Co-IP) followed by liquid chromatograph-mass spectrometry (LC-MS) identified that TTPAL exerted oncogenic functions via the interaction of Nicotinamide-N-methyl transferase (NNMT) and activated PI3K/AKT signaling pathway. Collectively, TTPAL plays a pivotal oncogenic role in gastric carcinogenesis through promoting PI3K/AKT pathway via cooperating with NNMT. TTPAL may serve as a prognostic biomarker of patients with GC.
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Affiliation(s)
- Wenxiu Liu
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongyan Gou
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaohong Wang
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Xiaoming Li
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxu Hu
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Hao Su
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Shengmian Li
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Jun Yu
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
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Zhang Y, Guo D. Epigenetic Variation Analysis Leads to Biomarker Discovery in Gastric Adenocarcinoma. Front Genet 2020; 11:551787. [PMID: 33363566 PMCID: PMC7753064 DOI: 10.3389/fgene.2020.551787] [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: 04/14/2020] [Accepted: 11/13/2020] [Indexed: 12/24/2022] Open
Abstract
As one of the most common malignant tumors worldwide, gastric adenocarcinoma (GC) and its prognosis are still poorly understood. Various genetic and epigenetic factors have been indicated in GC carcinogenesis. However, a comprehensive and in-depth investigation of epigenetic alteration in gastric cancer is still missing. In this study, we systematically investigated some key epigenetic features in GC, including DNA methylation and five core histone modifications. Data from The Cancer Genome Atlas Program and other studies (Gene Expression Omnibus) were collected, analyzed, and validated with multivariate statistical analysis methods. The landscape of epi-modifications in gastric cancer was described. Chromatin state transition analysis showed a histone marker shift in gastric cancer genome by employing a Hidden-Markov-Model based approach, indicated that histone marks tend to label different sets of genes in GC compared to control. An additive effect of these epigenetic marks was observed by integrated analysis with gene expression data, suggesting epigenetic modifications may cooperatively regulate gene expression. However, the effect of DNA methylation was found more significant without the presence of the five histone modifications in our study. By constructing a PPI network, key genes to distinguish GC from normal samples were identified, and distinct patterns of oncogenic pathways in GC were revealed. Some of these genes can also serve as potential biomarkers to classify various GC molecular subtypes. Our results provide important insights into the epigenetic regulation in gastric cancer and other cancers in general. This study describes the aberrant epigenetic variation pattern in GC and provides potential direction for epigenetic biomarker discovery.
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Affiliation(s)
- Yan Zhang
- State Key Laboratory of Agrobiotechnology, School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
| | - Dianjing Guo
- State Key Laboratory of Agrobiotechnology, School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
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4
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[An improved association analysis pipeline for tumor susceptibility variant in haplotype amplification area]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:1493-1499. [PMID: 33118521 PMCID: PMC7606235 DOI: 10.12122/j.issn.1673-4254.2020.10.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Haplotype amplification on germline variants is suggested to imply potential selective advantages and clonal expansion susceptibility and has become an important signature for seeking cancer susceptibility gene.Here we propose an improved association method that fully considers the haplotype amplification status. METHODS The haplotype amplification status was estimated by the variant allelic frequencies.We adopted a permutation test on variant allelic frequencies to divide the candidate variants into multiple groups.A likelihood clustering method was then applied to establish the neighborhood system of the hidden Markov random field framework.A filtering pipeline was introduced into the proposed method to further refine the candidate variants, including a Wilson's interval filter and a false discovery rate controller.The final candidate set along with the haplotype amplification status was collapsed into the weighted virtual sites for association tests. RESULTS Through simulated tests on a series of datasets, we compared the type Ⅰ error rates of different minor allele frequencies, which stably fell within 2%, suggesting good robustness of the algorithm.In addition, we compared another 5 published association approaches for Type-Ⅰ and Type-Ⅱ error rates with the proposed method, which resulted in the error rates all within 2%, demonstrating significant advantages and a good statistical ability of the proposed method. CONCLUSIONS The proposed method can accurately identify tumor susceptibility variants in haplotype amplification area with good robustness and stability.
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Loveday C, Litchfield K, Proszek PZ, Cornish AJ, Santo F, Levy M, Macintyre G, Holryod A, Broderick P, Dudakia D, Benton B, Bakir MA, Hiley C, Grist E, Swanton C, Huddart R, Powles T, Chowdhury S, Shipley J, O'Connor S, Brenton JD, Reid A, de Castro DG, Houlston RS, Turnbull C. Genomic landscape of platinum resistant and sensitive testicular cancers. Nat Commun 2020; 11:2189. [PMID: 32366847 PMCID: PMC7198558 DOI: 10.1038/s41467-020-15768-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 03/23/2020] [Indexed: 12/11/2022] Open
Abstract
While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.
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Affiliation(s)
- Chey Loveday
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Kevin Litchfield
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Paula Z Proszek
- The Centre for Molecular Pathology, The Royal Marsden NHS Trust, Sutton, London, UK
| | - Alex J Cornish
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Flavia Santo
- The Centre for Molecular Pathology, The Royal Marsden NHS Trust, Sutton, London, UK
| | - Max Levy
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Geoff Macintyre
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Amy Holryod
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Peter Broderick
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Darshna Dudakia
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Barbara Benton
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - Maise Al Bakir
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Crispin Hiley
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Emily Grist
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London, UK
- Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK
| | - Robert Huddart
- Academic Radiotherapy Unit, Institute of Cancer Research, London, UK
| | - Tom Powles
- Barts Cancer Institute, Queen Mary University, London, UK
| | - Simon Chowdhury
- Department of Oncology, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Janet Shipley
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Simon O'Connor
- The Centre for Molecular Pathology, The Royal Marsden NHS Trust, Sutton, London, UK
- Addenbrooke's Hospital, Cambridge, UK
- Department of Oncology, University of Cambridge, Cambridge, UK
| | - James D Brenton
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Alison Reid
- Academic Uro-oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, London, UK
| | | | - Richard S Houlston
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Clare Turnbull
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
- William Harvey Research Institute, Queen Mary University, London, UK.
- Guys and St Thomas' NHS Foundation Trust, Great Maze Pond, London, UK.
- Public Health England, National Cancer Registration and Analysis Service, London, UK.
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Jakubek YA, Chang K, Sivakumar S, Yu Y, Giordano MR, Fowler J, Huff CD, Kadara H, Vilar E, Scheet P. Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer. Nat Biotechnol 2020; 38:90-96. [PMID: 31685958 PMCID: PMC8082517 DOI: 10.1038/s41587-019-0297-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 09/25/2019] [Indexed: 01/21/2023]
Abstract
Mosaicism, the presence of subpopulations of cells bearing somatic mutations, is associated with disease and aging and has been detected in diverse tissues, including apparently normal cells adjacent to tumors. To analyze mosaicism on a large scale, we surveyed haplotype-specific somatic copy number alterations (sCNAs) in 1,708 normal-appearing adjacent-to-tumor (NAT) tissue samples from 27 cancer sites and in 7,149 blood samples from The Cancer Genome Atlas. We find substantial variation across tissues in the rate, burden and types of sCNAs, including those spanning entire chromosome arms. We document matching sCNAs in the NAT tissue and the adjacent tumor, suggesting a shared clonal origin, as well as instances in which both NAT tissue and tumor tissue harbor a gain of the same oncogene arising in parallel from distinct parental haplotypes. These results shed light on pan-tissue mutations characteristic of field cancerization, the presence of oncogenic processes adjacent to cancer cells.
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Affiliation(s)
- Y A Jakubek
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - K Chang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - S Sivakumar
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Y Yu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - M R Giordano
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Fowler
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - C D Huff
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - H Kadara
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - E Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - P Scheet
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Eftekhari A, Peivand Z, Saadat I, Saadat M. Association between Genetic Polymorphisms in Superoxide Dismutase Gene Family and Risk of Gastric Cancer. Pathol Oncol Res 2020; 26:335-339. [PMID: 30242560 DOI: 10.1007/s12253-018-0470-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 09/13/2018] [Indexed: 12/14/2022]
Abstract
To determine the association between the SOD1 (Ins/Del), SOD2 (rs2758339, rs5746136), and SOD3 (rs2536512) polymorphisms and the risk of gastric cancer the present study performed. This is a case-control study, including 159 patients with gastric cancer and 242 healthy controls. All subjects were Persian Muslims living in Shiraz (south west Iran). Frequency matching by age and gender was performed. Genomic DNA was extracted from whole blood. Genotypes of the study polymorphism were determined using polymerase chain reaction based methods. The SOD1 Ins/Del and SOD3 rs2536512 polymorphisms did not appear to have relationship with gastric cancer risk. Both SOD2 polymorphisms (rs2758339, rs5746136) showed significant association with the risk of gastric cancer, under assumption that the variant alleles act as dominant alleles. There was significant association between smoking habit and the risk of gastric cancer (OR = 2.54, 95% CI = 1.61-4.02, P < 0.001). Smoker individuals having two putative high-risk genotypes showed elevated risk of gastric cancer compared with nonsmokers without high-risk genotypes, (OR = 5.75, 95% CI = 1.59-20.6, P = 0.007). Assuming that smoking habit and the genotypes are independent risk factors, there was a significant linear trend for the numbers of risk factors and gastric cancer risk (χ2 = 22.9, P < 0.001). This study indicates that the SOD2 polymorphism (rs2758339, rs5746136) is associated with increased risk of gastric cancer, especially in smoker individuals.
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Affiliation(s)
- Alireza Eftekhari
- Department of Biology, College of Sciences, Shiraz University, Shiraz, 71467-13565, Iran
| | - Zahra Peivand
- Department of Biology, College of Sciences, Shiraz University, Shiraz, 71467-13565, Iran
| | - Iraj Saadat
- Department of Biology, College of Sciences, Shiraz University, Shiraz, 71467-13565, Iran.
| | - Mostafa Saadat
- Department of Biology, College of Sciences, Shiraz University, Shiraz, 71467-13565, Iran.
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Molecular Profiles and Metastasis Markers in Chinese Patients with Gastric Carcinoma. Sci Rep 2019; 9:13995. [PMID: 31570735 PMCID: PMC6769015 DOI: 10.1038/s41598-019-50171-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 09/06/2019] [Indexed: 02/08/2023] Open
Abstract
The goal of this work was to investigate the molecular profiles and metastasis markers in Chinese patients with gastric carcinoma (GC). In total, we performed whole exome sequencing (WES) on 74 GC patients with tumor and adjacent normal formalin-fixed, paraffin-embedded (FFPE) tissue samples. The mutation spectrum of these samples showed a high concordance with TCGA and other studies on GC. PTPRT is significantly associated with metastasis of GC, suggesting its predictive role in metastasis of GC. Patients carrying BRCA2 mutations tend not to metastasize, which may be related to their sensitivity to chemotherapy. Mutations in MACF1, CDC27, HMCN1, CDH1 and PDZD2 were moderately enriched in peritoneal metastasis (PM) samples. Furthermore, we found two genomic regions (1p36.21 and Xq26.3) were associated with PM of GC, and patients with amplification of 1p36.21 and Xq26.3 have a worse prognosis (P = 0.002, 0.01, respectively). Our analysis provides GC patients with potential markers for single and combination therapies.
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Chabanais J, Labrousse F, Chaunavel A, Germot A, Maftah A. POFUT1 as a Promising Novel Biomarker of Colorectal Cancer. Cancers (Basel) 2018; 10:cancers10110411. [PMID: 30380753 PMCID: PMC6266312 DOI: 10.3390/cancers10110411] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/26/2018] [Accepted: 10/27/2018] [Indexed: 12/18/2022] Open
Abstract
Background: While protein O-fucosyltransferase 1 (POFUT1) overexpression has been recently proposed as a potential biomarker for different cancer types, no study was carried out on POFUT1 implication in colorectal cancer (CRC). Methods: Data from 626 tumors and 51 non-tumor adjacent tissues available in FireBrowse had been used in this study. Statistical analyses on POFUT1 expression and gene copy number, NOTCH receptors (main targets of POFUT1 enzymatic activity) expression and association of POFUT1 and NOTCH1 expressions with clinical parameters were investigated. Data were completed by POFUT1 histological labeling on six tumor tissues from patients with CRC. Results: We found that POFUT1 is overexpressed from the stage I (p < 0.001) and 76.02% of tumors have a 20q11.21 amplification, associated in 90.13% of cases with a POFUT1 overexpression, compared to non-tumor adjacent tissues. The POFUT1 copy number in tumors is mainly between 2 and 3. POFUT1 is positively correlated with NOTCH1 (rs = 0.34, p < 0.001), NOTCH3 (rs = 0.087, p = 0.0297), and NOTCH4 (rs = 0.097, p = 0.0148) expressions, while negatively correlated with NOTCH2 expression (rs = −0.098, p = 0.0142). POFUT1 overexpression is markedly associated with rectal location, non-mucinous adenocarcinoma and cancer stages IV and M1. NOTCH1 overexpression is only associated with rectal location and non-mucinous adenocarcinoma. Conclusion: We conclude that POFUT1 is overexpressed in CRC from stage I, and its high expression is associated with metastatic process, probably through NOTCH pathway activation. Then, POFUT1 could represent a potential novel biomarker for CRC diagnosis.
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Affiliation(s)
- Julien Chabanais
- Glycosylation and Cell Differentiation, Limoges University, PEIRENE, EA 7500, F-87060 Limoges cedex, France.
| | - François Labrousse
- Department of Pathology, Limoges University Hospital, 87042 Limoges cedex, France.
| | - Alain Chaunavel
- Department of Pathology, Limoges University Hospital, 87042 Limoges cedex, France.
| | - Agnès Germot
- Glycosylation and Cell Differentiation, Limoges University, PEIRENE, EA 7500, F-87060 Limoges cedex, France.
| | - Abderrahman Maftah
- Glycosylation and Cell Differentiation, Limoges University, PEIRENE, EA 7500, F-87060 Limoges cedex, France.
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Bibi F, Ali I, Naseer MI, Ali Mohamoud HS, Yasir M, Alvi SA, Jiman-Fatani AA, Sawan A, Azhar EI. Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH). PLoS One 2018; 13:e0202576. [PMID: 30212456 PMCID: PMC6136709 DOI: 10.1371/journal.pone.0202576] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 08/06/2018] [Indexed: 02/08/2023] Open
Abstract
Background The present study was conducted to discover genetic imbalances such as DNA copy number variations (CNVs) associated with gastric cancer (GC) and to examine their association with different genes involved in the process of gastric carcinogenesis in Saudi population. Methods Formalin-fixed paraffin-embedded (FFPE) tissues samples from 33 gastric cancer patients and 15 normal gastric samples were collected. Early and late stages GC samples were genotyped and CNVs were assessed by using Illumina HumanOmni1-Quad v.1.0 BeadChip. Results Copy number gains were more frequent than losses throughout all GC samples compared to normal tissue samples. The mean number of the altered chromosome per case was 64 for gains and 40 for losses, and the median aberration length was 679115bp for gains and 375889bp for losses. We identified 7 high copy gain, 52 gains, 14 losses, 32 homozygous losses, and 10 copy neutral LOHs (loss of heterozygosities). Copy number gains were frequently detected at 1p36.32, 1q12, 1q22, 2p11.1, 4q23-q25, 5p12-p11, 6p21.33, 9q12-q21.11, 12q11-q12, 14q32.33, 16p13.3, 17p13.1, 17q25.3, 19q13.32, and losses at 1p36.23, 1p36.32, 1p32.1, 1q44, 3q25.2, 6p22.1, 6p21.33, 8p11.22, 10q22.1, 12p11.22, 14q32.12 and 16q24.2. We also identified 2 monosomy at chromosome 14 and 22, 52 partially trisomy and 22 whole chromosome 4 neutral loss of heterozygosities at 13q14.2-q21.33, 5p15.2-p15.1, 5q11.2-q13.2, 5q33.1-q34 and 3p14.2-q13.12. Furthermore, 11 gains and 2 losses at 1p36.32 were detected for 11 different GC samples and this region has not been reported before in other populations. Statistical analysis confirms significant association of H. pylori infection with T4 stage of GC as compare to control and other stages. Conclusions We found that high frequency of copy number gains and losses at 1p36.23, 1p32.1, 1p36.32, 3q25.2, 6p21.33 and 16q24.2 may be common events in gastric cancer. While novel CNVs at 1p36.32 harbouring PRDM16, TP73 and TP73-AS1 genes showed 11 gains and 2 losses for 11 different GC cases and this region is not reported yet in Database of Genomic Variants may be specific to Saudi population.
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Affiliation(s)
- Fehmida Bibi
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
- * E-mail:
| | - Isse Ali
- Centre for Computational Intelligence (CCI), Faculty of Technology, De Montfort University, United Kingdom
| | - Muhammad Imran Naseer
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hussein Sheikh Ali Mohamoud
- Department of Clinical Genetics, St George’s University Hospitals NHS Foundation Trust, Cranmer Terrace London, United Kingdom
| | - Muhammad Yasir
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Sana Akhtar Alvi
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Asif Ahmed Jiman-Fatani
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali Sawan
- Department of Anatomical Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Esam Ibraheem Azhar
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process. Oncotarget 2018; 7:85393-85410. [PMID: 27863420 PMCID: PMC5356744 DOI: 10.18632/oncotarget.13381] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 10/27/2016] [Indexed: 12/16/2022] Open
Abstract
We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process.
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Mytar B, Stec M, Szatanek R, Węglarczyk K, Szewczyk K, Szczepanik A, Drabik G, Baran J, Siedlar M, Baj-Krzyworzeka M. Characterization of human gastric adenocarcinoma cell lines established from peritoneal ascites. Oncol Lett 2018; 15:4849-4858. [PMID: 29552124 PMCID: PMC5840753 DOI: 10.3892/ol.2018.7995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 12/28/2017] [Indexed: 01/01/2023] Open
Abstract
The three cell lines, designated as gastric cancer (GC)1401, GC1415 and GC1436 were derived from peritoneal effusions from patients with gastric adenocarcinoma. Cell lines were established in tissue culture and in immunodeficient, non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. All cell lines were cultured in Dulbecco's modified Eagle's medium supplemented with 5% fetal bovine serum. These cell lines were grown as an adherent monolayer with doubling time ranging between 25 h (GC1436 cell line) and 30–34 h (GC1401 and GC1415, respectively). All cells showed morphological features of epithelial-like cells, forming sheets of polygonal cells. Chromosomal analysis showed that the modal numbers ranged from 52 (GC1401), 51–56 (GC1415) and 106 (GC1436). High heterogeneity, resulting from several structural and numerical chromosomal abnormalities were evident in all cell lines. The surface marker expression suggested a tumor origin of the cells, and indicated the intestinal phenotype of a GC (CD10+, MUC1). All three cell lines were tumorigenic but not metastatic, in vivo, in NOD/SCID mice. The lack of metastatic potential was suggested by the lack of aldehyde dehydrogenase 1A1 activity. In conclusion, these newly established GC cell lines widen the feasibility of the functional studies on biology of GC as well as drug testing for potential therapeutic purposes.
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Affiliation(s)
- Bożenna Mytar
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Małgorzata Stec
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Rafał Szatanek
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Kazimierz Węglarczyk
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Katarzyna Szewczyk
- Department of Medical Genetics Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Antoni Szczepanik
- First Department of General Gastrointestinal and Oncology Surgery, Jagiellonian University Medical College, 30-001 Krakow, Poland
| | - Grażyna Drabik
- Department of Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Jarek Baran
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
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Gigek CO, Calcagno DQ, Rasmussen LT, Santos LC, Leal MF, Wisnieski F, Burbano RR, Lourenço LG, Lopes-Filho GJ, Smith MAC. Genetic variants in gastric cancer: Risks and clinical implications. Exp Mol Pathol 2017; 103:101-111. [PMID: 28736214 DOI: 10.1016/j.yexmp.2017.07.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 07/03/2017] [Accepted: 07/19/2017] [Indexed: 12/14/2022]
Abstract
Cancer is a multifactorial disease that involves many molecular alterations. Gastric cancer (GC) is the third leading cause of cancer death worldwide. GC is a highly heterogeneous disease with different molecular and genetics features. Therefore, this review focuses on an overview of the genetic aspects of gastric cancer by highlighting the important impact and role of deletions and/or duplications of chromosomal segments, genomic variants, H. pylori infection and interleukin variants, as found in gene expression and newly proposed molecular classification studies. The challenge is to better understand the mechanisms and different pathways that lead to the development and progression of GC.
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Affiliation(s)
- Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), CEP 04023-900 São Paulo, Brazil; Disciplina de Gastroenterologia Cirúrgica, Universidade Federal de São Paulo (UNIFESP), CEP: 04024-002 São Paulo, Brazil.
| | - Danielle Queiroz Calcagno
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará (UFPA), CEP: 66073-000 Belém, Pará, Brazil
| | | | - Leonardo Caires Santos
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), CEP 04023-900 São Paulo, Brazil
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), CEP 04023-900 São Paulo, Brazil; Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo (UNIFESP), CEP 04038-032 São Paulo, Brazil
| | - Fernanda Wisnieski
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), CEP 04023-900 São Paulo, Brazil
| | | | - Laercio Gomes Lourenço
- Disciplina de Gastroenterologia Cirúrgica, Universidade Federal de São Paulo (UNIFESP), CEP: 04024-002 São Paulo, Brazil
| | - Gaspar Jesus Lopes-Filho
- Disciplina de Gastroenterologia Cirúrgica, Universidade Federal de São Paulo (UNIFESP), CEP: 04024-002 São Paulo, Brazil
| | - Marilia Arruda Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), CEP 04023-900 São Paulo, Brazil
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Mahas A, Potluri K, Kent MN, Naik S, Markey M. Copy number variation in archival melanoma biopsies versus benign melanocytic lesions. Cancer Biomark 2017; 16:575-97. [PMID: 27002761 DOI: 10.3233/cbm-160600] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Skin melanocytes can give rise to benign and malignant neoplasms. Discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. However, previous studies have shown that in contrast to benign nevi, melanoma demonstrates pervasive chromosomal aberrations. OBJECTIVE This substantial difference between melanoma and benign nevi can be exploited to discriminate between melanoma and benign nevi. METHODS Array-comparative genomic hybridization (aCGH) is an approach that can be used on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues to assess the entire genome for the presence of changes in DNA copy number. In this study, high resolution, genome-wide single-nucleotide polymorphism (SNP) arrays were utilized to perform comprehensive and detailed analyses of recurrent copy number aberrations in 41 melanoma samples in comparison with 21 benign nevi. RESULTS We found statistically significant copy number gains and losses within melanoma samples. Some of the identified aberrations are previously implicated in melanoma. Moreover, novel regions of copy number alterations were identified, revealing new candidate genes potentially involved in melanoma pathogenesis. CONCLUSIONS Taken together, these findings can help improve melanoma diagnosis and introduce novel melanoma therapeutic targets.
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Affiliation(s)
- Ahmed Mahas
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
| | - Keerti Potluri
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
| | - Michael N Kent
- Department of Dermatology, Wright State University Boonshoft School of Medicine, Dayton, OH, USA.,Dermatopathology Laboratory of Central States, Dayton, OH, USA
| | - Sameep Naik
- Dermatopathology Laboratory of Central States, Dayton, OH, USA
| | - Michael Markey
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
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15
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Calcagno DQ, Takeno SS, Gigek CO, Leal MF, Wisnieski F, Chen ES, Araújo TMT, Lima EM, Melaragno MI, Demachki S, Assumpção PP, Burbano RR, Smith MC. Identification of IL11RA and MELK amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines. World J Gastroenterol 2016; 22:9506-9514. [PMID: 27920471 PMCID: PMC5116594 DOI: 10.3748/wjg.v22.i43.9506] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/10/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To identify common copy number alterations on gastric cancer cell lines.
METHODS Four gastric cancer cell lines (ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence in situ hybridization analysis using the bacterial artificial chromosome clone and quantitative real time PCR analysis.
RESULTS The amplification of 9p13.3 was detected in all cell lines by both methodologies. An increase in the copy number of 9p13.3 was also confirmed by fluorescence in situ hybridization analysis. Moreover, the interleukin 11 receptor alpha (IL11RA) and maternal embryonic leucine zipper kinase (MELK) genes, which are present in the 9p13.3 amplicon, revealed gains of the MELK gene in all the cell lines studied. Additionally, a gain in the copy number of IL11RA and MELK was observed in 19.1% (13/68) and 55.9% (38/68) of primary gastric adenocarcinoma samples, respectively.
CONCLUSION The characterization of a small gain region at 9p13.3 in gastric cancer cell lines and primary gastric adenocarcinoma samples has revealed MELK as a candidate target gene that is possibly related to the development of gastric cancer.
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Chan THM, Qamra A, Tan KT, Guo J, Yang H, Qi L, Lin JS, Ng VHE, Song Y, Hong H, Tay ST, Liu Y, Lee J, Rha SY, Zhu F, So JBY, Teh BT, Yeoh KG, Rozen S, Tenen DG, Tan P, Chen L. ADAR-Mediated RNA Editing Predicts Progression and Prognosis of Gastric Cancer. Gastroenterology 2016; 151:637-650.e10. [PMID: 27373511 PMCID: PMC8286172 DOI: 10.1053/j.gastro.2016.06.043] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 06/23/2016] [Accepted: 06/24/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUD & AIMS Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown. METHODS In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy. RESULTS Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL. CONCLUSIONS Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
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Affiliation(s)
- Tim Hon Man Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Aditi Qamra
- Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kar Tong Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Jing Guo
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Lihua Qi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Jaymie Siqi Lin
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Vanessa Hui En Ng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Yangyang Song
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Huiqi Hong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Su Ting Tay
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore
| | - Yujing Liu
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore,Singapore–Massachusetts Institute of Technology Alliance, Singapore
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sun Yong Rha
- Yonsei Cancer Center, Seodaemun-gu, Seoul, South Korea
| | - Feng Zhu
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jimmy Bok Yan So
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Bin Tean Teh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore,Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | - Khay Guan Yeoh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore,Department of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Steve Rozen
- Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore,Centre for Computational Biology, Duke–National University of Singapore Graduate Medical School, Singapore
| | - Daniel G. Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts
| | - Patrick Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Cellular and Molecular Research, National Cancer Centre, Singapore; Genome Institute of Singapore, Singapore.
| | - Leilei Chen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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17
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Clinicopathological characterisation of small (2 cm or less) proximal and distal gastric carcinomas in a Chinese population. Pathology 2016; 47:526-32. [PMID: 26166663 PMCID: PMC4699347 DOI: 10.1097/pat.0000000000000276] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SummaryClinicopathological characteristics of small gastric carcinoma have not been well defined in Chinese patients. The aim of this study was to investigate and compare small proximal (PGC, n = 111) with distal (DGC, n = 202) gastric carcinoma in 313 consecutive surgically resected small (≤2 cm) gastric carcinomas diagnosed with the WHO criteria. PGC patients were significantly older (average age 63 years versus 59 in DGCs) with a male/female ratio of 3:1. Most tumours were clustered along the lesser curvature (74% in PGCs and 65% in DGCs). Compared to DGCs, PGCs showed a protruded gross pattern significantly more frequently and were significantly better differentiated with a significantly wider histomorphological spectrum. Surprisingly, PGCs were composed of significantly fewer signet-ring cell carcinomas (1% versus 16% in DGCs) but were significantly more deeply invasive, compared to DGCs. Lymph node metastasis was detected in 23% overall, but was significantly less frequent in PGCs (16%) than in DGCs (26%) (p < 0.05). However, the difference in survival between the two groups was not statistically significant. Our results demonstrate that in Chinese patients, PGCs display distinct clinicopathological characteristics, compared to DGCs.
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18
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Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus. Mod Pathol 2016; 29:227-39. [PMID: 26743478 DOI: 10.1038/modpathol.2015.153] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Revised: 11/22/2015] [Accepted: 11/23/2015] [Indexed: 12/14/2022]
Abstract
Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions.
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19
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Mello AA, Leal MF, Rey JA, Pinto GR, Lamarão LM, Montenegro RC, Alves APNN, Assumpção PP, Borges BDN, Smith MC, Burbano RR. Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis. PLoS One 2015; 10:e0140492. [PMID: 26460485 PMCID: PMC4604160 DOI: 10.1371/journal.pone.0140492] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 09/25/2015] [Indexed: 12/29/2022] Open
Abstract
Kinases are downstream modulators and effectors of several cellular signaling cascades and play key roles in the development of neoplastic disease. In this study, we aimed to evaluate SRC, LYN and CKB protein and mRNA expression, as well as their promoter methylation, in gastric cancer. We found elevated expression of SRC and LYN kinase mRNA and protein but decreased levels of CKB kinase, alterations that may have a role in the invasiveness and metastasis of gastric tumors. Expression of the three studied kinases was also associated with MYC oncogene expression, a possible biomarker for gastric cancer. To understand the mechanisms that regulate the expression of these genes, we evaluated the DNA promoter methylation of the three kinases. We found that reduced SRC and LYN methylation and increased CKB methylation was associated with gastric cancer. The reduced SRC and LYN methylation was associated with increased levels of mRNA and protein expression, suggesting that DNA methylation is involved in regulating the expression of these kinases. Conversely, reduced CKB methylation was observed in samples with reduced mRNA and protein expression, suggesting CKB expression was found to be only partly regulated by DNA methylation. Additionally, we found that alterations in the DNA methylation pattern of the three studied kinases were also associated with the gastric cancer onset, advanced gastric cancer, deeper tumor invasion and the presence of metastasis. Therefore, SRC, LYN and CKB expression or DNA methylation could be useful markers for predicting tumor progression and targeting in anti-cancer strategies.
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Affiliation(s)
- Adriano Azevedo Mello
- Centro de Ciências Biológicas e da Saúde, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- * E-mail:
| | - Juan Antonio Rey
- Laboratorio de Oncogenética Molecular, Hospital Universitario La Paz, Madrid, Madrid, Spain
| | | | - Leticia Martins Lamarão
- Laboratório de Testes de Ácidos Nucleicos, Fundação Centro de Hemoterapia e Hematologia do Pará, Belém, PA, Brazil
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | | | | | - Paulo Pimentel Assumpção
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | - Barbara do Nascimento Borges
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Centro de Tecnologia Agropecuária, Instituto Socioambiental e dos Recursos Hídricos, Universidade Federal Rural da Amazônia, Belém, PA, Brazil
| | - Marília Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Rommel Rodriguez Burbano
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
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Hudler P. Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol 2015; 21:10510-10527. [PMID: 26457012 PMCID: PMC4588074 DOI: 10.3748/wjg.v21.i37.10510] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
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21
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Farid SG, Morris-Stiff G. "OMICS" technologies and their role in foregut primary malignancies. Curr Probl Surg 2015; 52:409-41. [PMID: 26527526 DOI: 10.1067/j.cpsurg.2015.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 08/03/2015] [Indexed: 12/18/2022]
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22
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Deciphering the Correlation between Breast Tumor Samples and Cell Lines by Integrating Copy Number Changes and Gene Expression Profiles. BIOMED RESEARCH INTERNATIONAL 2015; 2015:901303. [PMID: 26273658 PMCID: PMC4529967 DOI: 10.1155/2015/901303] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/16/2015] [Accepted: 01/26/2015] [Indexed: 02/02/2023]
Abstract
Breast cancer is one of the most common cancers with high incident rate and high mortality rate worldwide. Although different breast cancer cell lines were widely used in laboratory investigations, accumulated evidences have indicated that genomic differences exist between cancer cell lines and tissue samples in the past decades. The abundant molecular profiles of cancer cell lines and tumor samples deposited in the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas now allow a systematical comparison of the breast cancer cell lines with breast tumors. We depicted the genomic characteristics of breast primary tumors based on the copy number variation and gene expression profiles and the breast cancer cell lines were compared to different subgroups of breast tumors. We identified that some of the breast cancer cell lines show high correlation with the tumor group that agrees with previous knowledge, while a big part of them do not, including the most used MCF7, MDA-MB-231, and T-47D. We presented a computational framework to identify cell lines that mostly resemble a certain tumor group for the breast tumor study. Our investigation presents a useful guide to bridge the gap between cell lines and tumors and helps to select the most suitable cell line models for personalized cancer studies.
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Bergmann F, Aulmann S, Sipos B, Kloor M, von Heydebreck A, Schweipert J, Harjung A, Mayer P, Hartwig W, Moldenhauer G, Capper D, Dyckhoff G, Freier K, Herpel E, Schleider A, Schirmacher P, Mechtersheimer G, Klöppel G, Bläker H. Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases. Virchows Arch 2014; 465:661-72. [PMID: 25298229 DOI: 10.1007/s00428-014-1657-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 08/15/2014] [Accepted: 09/12/2014] [Indexed: 12/14/2022]
Abstract
Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.
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Affiliation(s)
- Frank Bergmann
- Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, D-69120, Heidelberg, Germany,
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24
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Tsai PC, Huang SW, Tsai HL, Ma CJ, Hou MF, Yang IP, Wang YS, Juo SHH, Wang JY. The association between DNA copy number aberrations at chromosome 5q22 and gastric cancer. PLoS One 2014; 9:e106624. [PMID: 25210923 PMCID: PMC4161348 DOI: 10.1371/journal.pone.0106624] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 07/30/2014] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Gastric cancer is common cancer. Discovering novel genetic biomarkers might help to identify high-risk individuals. Copy number variation (CNV) has recently been shown to influence risk for several cancers. The aim of the present study was sought to test the association between copy number at a variant region and GC. METHODS A total of 110 gastric cancer patients and 325 healthy volunteers were enrolled in this study. We searched for a CNV and found a CNV (Variation 7468) containing part of the APC gene, the SRP19 gene and the REEP5 gene. We chose four probes targeting at APC-intron8, APC-exon9, SRP19 and REEP5 to interrogate this CNV. Specific Taqman probes labeled by different reporter fluorophores were used in a real-time PCR platform to obtain copy number. Both the original non-integer data and transformed integer data on copy number were used for analyses. RESULTS Gastric caner patients had a lower non-integer copy number than controls for the APC-exon9 probe (Adjusted p = 0.026) and SRP19 probe (Adjusted p = 0.002). The analysis of integer copy number yielded a similar pattern although less significant (Adjusted p = 0.07 for APC-exon9 probe and Adjusted p = 0.02 for SRP19 probe). CONCLUSIONS Losses of a CNV at 5q22, especially in the DNA region surrounding APC-exon 9, may be associated with a higher risk of gastric cancer.
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Affiliation(s)
- Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Szu-Wei Huang
- Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Cheng-Jen Ma
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Feng Hou
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - I-Ping Yang
- Department of Nursing, Shu-Zen College of Medicine and Management, Kaohsiung, Taiwan
| | - Yung-Song Wang
- Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Suh-Hang Hank Juo
- Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Abstract
BACKGROUND Gastric cancer is a heterogeneous disease with respect to its molecular and histopathological features. Proximal gastric carcinoma (PGC) and distal gastric carcinoma (DGC) are two distinct clinical entities, suggesting the existence of different pathogenic mechanisms. PGC arises in a narrow region of the proximal stomach below the gastroesophageal junction. It accounts for around half of gastric cancers in men, with an increasing incidence worldwide and a predominance in elderly males. SUMMARY At present, the pathogenic mechanisms involved in the onset of PGC remain unknown. This mini-review presents the most recent findings on the pathology and natural history of this widespread and frequently fatal cancer. KEY MESSAGE PGC has unique clinicopathological characteristics distinct from esophageal adenocarcinoma and DGC. PRACTICAL IMPLICATIONS Patients with a high risk for PGC, such as elderly obese men, should undergo upper endoscopy for early detection and appropriate endoscopic therapy in the early stages of disease. Once it has progressed, the cancer is more easily spread, although the current staging systems are not perfectly adapted to the disease. PGC should be staged and treated as a gastric cancer. A separate staging system and genomic studies on this cancer are urgently needed for optimal patient management and appropriate disease prevention.
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Affiliation(s)
- Qin Huang
- Department of Pathology and Laboratory Medicine, Veterans Affairs Boston Healthcare System and Harvard Medical School, West Roxbury, Mass., USA
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26
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Wang K, Yuen ST, Xu J, Lee SP, Yan HHN, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan ASY, Tsui WY, Ho SL, Chan AKW, Man JLK, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GHW, Xie T, Fernandez J, Li VSW, Clevers H, Rejto PA, Mao M, Leung SY. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 2014; 46:573-82. [PMID: 24816253 DOI: 10.1038/ng.2983] [Citation(s) in RCA: 823] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 04/18/2014] [Indexed: 02/08/2023]
Abstract
Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.
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Affiliation(s)
- Kai Wang
- 1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2]
| | - Siu Tsan Yuen
- 1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2]
| | - Jiangchun Xu
- 1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2] [3]
| | - Siu Po Lee
- 1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2]
| | - Helen H N Yan
- 1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2]
| | - Stephanie T Shi
- External Research Solutions, Pfizer Worldwide Research and Development, San Diego, California, USA
| | - Hoi Cheong Siu
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Shibing Deng
- Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA
| | - Kent Man Chu
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Simon Law
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Kok Hoe Chan
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Annie S Y Chan
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Wai Yin Tsui
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Siu Lun Ho
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Anthony K W Chan
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Jonathan L K Man
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Valentina Foglizzo
- Division of Stem Cell Biology and Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, UK
| | - Man Kin Ng
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - April S Chan
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Yick Pang Ching
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Grace H W Cheng
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Tao Xie
- Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA
| | - Julio Fernandez
- Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA
| | - Vivian S W Li
- Division of Stem Cell Biology and Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, UK
| | - Hans Clevers
- Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Paul A Rejto
- Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA
| | - Mao Mao
- 1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2]
| | - Suet Yi Leung
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
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27
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Ali Hassan NZ, Mokhtar NM, Kok Sin T, Mohamed Rose I, Sagap I, Harun R, Jamal R. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues. PLoS One 2014; 9:e92553. [PMID: 24694993 PMCID: PMC3973632 DOI: 10.1371/journal.pone.0092553] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 02/24/2014] [Indexed: 12/24/2022] Open
Abstract
Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV) and gene expression in colorectal cancer (CRC) samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.
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Affiliation(s)
- Nur Zarina Ali Hassan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
- * E-mail: (NMM); (RJ)
| | - Teow Kok Sin
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia
| | - Isa Mohamed Rose
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ismail Sagap
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Roslan Harun
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia
- Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia
- * E-mail: (NMM); (RJ)
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28
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Sonoda A, Mukaisho KI, Nakayama T, Diem VTN, Hattori T, Andoh A, Fujiyama Y, Sugihara H. Genetic lineages of undifferentiated-type gastric carcinomas analysed by unsupervised clustering of genomic DNA microarray data. BMC Med Genomics 2013; 6:25. [PMID: 23866769 PMCID: PMC3728264 DOI: 10.1186/1755-8794-6-25] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 07/11/2013] [Indexed: 12/13/2022] Open
Abstract
Background It is suspected that early gastric carcinoma (GC) is a dormant variant that rarely progresses to advanced GC. We demonstrated that the dormant and aggressive variants of tubular adenocarcinomas (TUBs) of the stomach are characterized by loss of MYC and gain of TP53 and gain of MYC and/or loss of TP53, respectively. The aim of this study is to determine whether this is also the case in undifferentiated-type GCs (UGCs) of different genetic lineages: one with a layered structure (LS+), derived from early signet ring cell carcinomas (SIGs), and the other, mostly poorly differentiated adenocarcinomas, without LS but with a minor tubular component (TC), dedifferentiated from TUBs (LS−/TC+). Methods Using 29 surgically resected stomachs with 9 intramucosal and 20 invasive UGCs (11 LS+ and 9 LS−/TC+), 63 genomic DNA samples of mucosal and invasive parts and corresponding reference DNAs were prepared from formalin-fixed, paraffin-embedded tissues with laser microdissection, and were subjected to array-based comparative genomic hybridization (aCGH), using 60K microarrays, and subsequent unsupervised, hierarchical clustering. Of 979 cancer-related genes assessed, we selected genes with mean copy numbers significantly different between the two major clusters. Results Based on similarity in genomic copy-number profile, the 63 samples were classified into two major clusters. Clusters A and B, which were rich in LS+ UGC and LS−/TC+ UGC, respectively, were discriminated on the basis of 40 genes. The aggressive pattern was more frequently detected in LS−/TC+ UGCs, (20/26; 77%), than in LS+UGCs (17/37; 46%; P = 0.0195), whereas no dormant pattern was detected in any of the UGC samples. Conclusions In contrast to TUBs, copy number alterations of MYC and TP53 exhibited an aggressive pattern in LS+ SIG at early and advanced stages, indicating that early LS+ UGCs inevitably progress to an advanced GC. Cluster B (enriched in LS−/TC+) exhibited more frequent gain of driver genes and a more frequent aggressive pattern than cluster A, suggesting potentially worse prognosis in UGCs of cluster B.
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Affiliation(s)
- Ayano Sonoda
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Otsu 520-2192, Japan
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Tänzer M, Liebl M, Quante M. Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. Pharmacol Ther 2013; 140:133-47. [PMID: 23791941 DOI: 10.1016/j.pharmthera.2013.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.
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Affiliation(s)
- Marc Tänzer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany
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30
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Uppal DS, Powell SM. Genetics/genomics/proteomics of gastric adenocarcinoma. Gastroenterol Clin North Am 2013; 42:241-60. [PMID: 23639639 DOI: 10.1016/j.gtc.2013.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hereditary diffuse gastric cancer can be caused by epithelial cadherin mutations for which genetic testing is available. Inherited cancer predisposition syndromes including Lynch, Li-Fraumeni, and Peutz-Jeghers syndromes, can be associated with gastric cancer. Chromosomal and microsatellite instability occur in gastric cancers. Several consistent genetic and molecular alterations including chromosomal instability, microsatellite instability, and epigenetic alterations have been identified in gastric cancers. Biomarkers and molecular profiles are being discovered with potential for diagnostic, prognostic, and treatment guidance implications.
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Affiliation(s)
- Dushant S Uppal
- Division of Gastroenterology/Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA 22908-0708, USA
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31
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Zouridis H, Deng N, Ivanova T, Zhu Y, Wong B, Huang D, Wu YH, Wu Y, Tan IB, Liem N, Gopalakrishnan V, Luo Q, Wu J, Lee M, Yong WP, Goh LK, Teh BT, Rozen S, Tan P. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci Transl Med 2013; 4:156ra140. [PMID: 23076357 DOI: 10.1126/scitranslmed.3004504] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epigenetic alterations are fundamental hallmarks of cancer genomes. We surveyed the landscape of DNA methylation alterations in gastric cancer by analyzing genome-wide CG dinucleotide (CpG) methylation profiles of 240 gastric cancers (203 tumors and 37 cell lines) and 94 matched normal gastric tissues. Cancer-specific epigenetic alterations were observed in 44% of CpGs, comprising both tumor hyper- and hypomethylation. Twenty-five percent of the methylation alterations were significantly associated with changes in tumor gene expression. Whereas most methylation-expression correlations were negative, several positively correlated methylation-expression interactions were also observed, associated with CpG sites exhibiting atypical transcription start site distances and gene body localization. Methylation clustering of the tumors revealed a CpG island methylator phenotype (CIMP) subgroup associated with widespread hypermethylation, young patient age, and adverse patient outcome in a disease stage-independent manner. CIMP cell lines displayed sensitivity to 5-aza-2'-deoxycytidine, a clinically approved demethylating drug. We also identified long-range regions of epigenetic silencing (LRESs) in CIMP tumors. Combined analysis of the methylation, gene expression, and drug treatment data suggests that certain LRESs may silence specific genes within the region, rather than all genes. Finally, we discovered regions of long-range tumor hypomethylation, associated with increased chromosomal instability. Our results provide insights into the epigenetic impact of environmental and biological agents on gastric epithelial cells, which may contribute to cancer.
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Affiliation(s)
- Hermioni Zouridis
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore
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Liang JW, Shi ZZ, Zhang TT, Hao JJ, Wang Z, Wang XM, Yang H, Wang MR, Zhou ZX, Zhang Y. Analysis of genomic aberrations associated with the clinicopathological parameters of rectal cancer by array‑based comparative genomic hybridization. Oncol Rep 2013; 29:1827-34. [PMID: 23440507 DOI: 10.3892/or.2013.2296] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 01/28/2013] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to screen and identify the chromosomal aberrations that are correlated with clinicopathological characteristics of rectal cancer using array-based comparative genomic hybridization (array-CGH). Forty-eight fresh frozen tumor tissues of rectal carcinoma were analyzed by array-CGH. The results showed that most frequent gains included 8q24.3, 20q11.21-q13.32, 20q13.33 and losses in 8p23.3-p12, 17p13.1-p12 and 18q11.2-q23 were noted. Fourteen amplifications and seven homozygous deletions were identified in the rectal cancer samples. Losses of 4p16.1-p15.31, 8p21.1-p12 and gains of 7p12.3-p12.1 and 13q33.1-q34 were associated with positive lymph node status and advanced clinical stage (stages III and IV). The 17q24.2-25.3 gain was more frequent in patients with distant metastasis. Integrated analysis indicated that overexpression of PDP1, TRIB1, C13orf27, FOXA2, PMEPA1 and PHACTR3 was associated with gains, and underexpression of FHOD, SMAD4 and BCL2 was associated with losses. Pathway enrichment analysis showed that pathways of nitrogen metabolism, oxidative phosphorylation, cell cycle, maturity onset diabetes of young, cytokine-cytokine receptor interaction, MAPK signaling pathway and dentatorubropallidoluysian atrophy were influenced by copy number changes.
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Affiliation(s)
- Jian-Wei Liang
- Department of Abdominal Surgical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
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Liu YY, Chen HY, Zhang ML, Tian D, Li S, Lee JY. Loss of fragile histidine triad and amplification of 1p36.22 and 11p15.5 in primary gastric adenocarcinomas. World J Gastroenterol 2012; 18:4522-32. [PMID: 22969225 PMCID: PMC3435777 DOI: 10.3748/wjg.v18.i33.4522] [Citation(s) in RCA: 7] [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: 12/19/2011] [Revised: 02/01/2012] [Accepted: 04/13/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the genomic copy number alterations that may harbor key driver genes in gastric tumorigenesis.
METHODS: Using high-resolution array comparative genomic hybridization (CGH), we investigated the genomic alterations of 20 advanced primary gastric adenocarcinomas (seventeen tubular and three mucinous) of Chinese patients from the Jilin province. Ten matching adjacent normal regions from the same patients were also studied.
RESULTS: The most frequent imbalances detected in these cancer samples were gains of 3q26.31-q27.2, 5p, 8q, 11p, 18p, 19q and 20q and losses of 3p, 4p, 18q and 21q. The use of high-resolution array CGH increased the resolution and sensitivity of the observed genomic changes and identified focal genetic imbalances, which included 54 gains and 16 losses that were smaller than 1 Mb in size. The most interesting focal imbalances were the intergenic loss/homozygous deletion of the fragile histidine triad gene and the amplicons 11q13, 18q11.2 and 19q12, as well as the novel amplicons 1p36.22 and 11p15.5.
CONCLUSION: These regions, especially the focal amplicons, may harbor key driver genes that will serve as biomarkers for either the diagnosis or the prognosis of gastric cancer, and therefore, a large-scale investigation is recommended.
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34
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Buffart TE, Carvalho B, van Grieken NCT, van Wieringen WN, Tijssen M, Kranenbarg EMK, Verheul HMW, Grabsch HI, Ylstra B, van de Velde CJH, Meijer GA. Losses of chromosome 5q and 14q are associated with favorable clinical outcome of patients with gastric cancer. Oncologist 2012; 17:653-62. [PMID: 22531355 DOI: 10.1634/theoncologist.2010-0379] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To improve the clinical outcome of patients with gastric cancer, intensified combination strategies are currently in clinical development, including combinations of more extensive surgery, (neo)adjuvant chemotherapy, and radiotherapy. The present study used DNA copy number profiling to identify subgroups of patients with different clinical outcomes. We hypothesize that, by identification of subgroups, individual treatment strategies can be selected to improve clinical outcome and to reduce unnecessary treatment toxicity for patients with gastric cancer. EXPERIMENTAL DESIGN DNA from 206 gastric cancer patients was isolated and analyzed by genomewide array comparative genomic hybridization. DNA copy number profiles were correlated with lymph node status and patient survival. In addition, heat shock protein 90 (HSP90) expression was analyzed and correlated with survival in 230 gastric cancer patients. RESULTS Frequent (>20%) DNA copy number gains and losses were observed on several chromosomal regions. Losses on 5q11.2-q31.3 and 14q32.11-q32.33 (14% of patients) were correlated with good clinical outcome in univariate and multivariate analyses, with a median disease-free survival interval of 9.2 years. In addition, loss of expression of HSP90, located on chromosome 14q32.2, was correlated with better patient survival. CONCLUSION Genomewide DNA copy number profiling allowed the identification of a subgroup of gastric cancer patients, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 or low HSP90 protein expression, with an excellent clinical outcome after surgery alone. We hypothesize that this subgroup of patients most likely will not benefit from (neo)adjuvant systemic treatment and/or radiotherapy, whereas anti-HSP90 therapy may have clinical potential in patients with HSP90-expressing gastric cancer, pending validation in an independent dataset.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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Ottini L, Falchetti M, Nesi G. Gene Signatures in Gastric Cancer. DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC VALUE OF GENE SIGNATURES 2012:95-113. [DOI: 10.1007/978-1-61779-358-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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36
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Sanjmyatav J, Junker K, Matthes S, Muehr M, Sava D, Sternal M, Wessendorf S, Kreuz M, Gajda M, Wunderlich H, Schwaenen C. Identification of genomic alterations associated with metastasis and cancer specific survival in clear cell renal cell carcinoma. J Urol 2011; 186:2078-83. [PMID: 21944119 DOI: 10.1016/j.juro.2011.06.050] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Indexed: 01/17/2023]
Abstract
PURPOSE We identified regions of DNA copy number changes that are significantly associated with metastasis and clinical outcome in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS We analyzed 53 primary clear cell renal cell carcinomas, including 31 metastasized and 22 nonmetastasized tumors, by array comparative genomic hybridization with a median resolution of 1 to 1.5 Mbp. To validate copy number aberrations with potential prognostic value we performed fluorescence in situ hybridization analysis using commercially available fluorescent probes. RESULTS We identified 5 recurrent chromosomal aberrations that were significantly associated with metastasis, including gains of 1q21.3, 12q13.12, 12q13.3q14.1 and 20q11.21q13.2, and loss of 9p21.3p24.1. The most prominent of them with the highest OR for metastatic risk were loss of 9p21.3p24.1, and gains of 1q21.3 and 20q11.21q13.32. Eight alterations involving chromosomes 7, 9, 12, 16 and 20 significantly correlated with shortened cancer specific survival. The lowest p values on Kaplan-Meier analysis showed losses of 9p21.3p24.1 and 9q32q33.1, and gains of 7q36.3 and 20q11.21q13.32. Fluorescence in situ hybridization done in the same cohort for the 4 select regions 1q21.3, 7q36.3, 9p21.3p24.1 and 20q11.21q13.32 clearly confirmed the results of array comparative genomic hybridization. CONCLUSIONS Data suggest that specific chromosomal alterations in clear cell renal cell carcinoma can be used to predict metastasis and cancer specific survival in patients with clear cell renal cell carcinoma. It seems possible to design a combined fluorescence in situ hybridization assay based on these genetic targets for outcome prediction, which can be used for routine diagnostics.
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Affiliation(s)
- Jimsgene Sanjmyatav
- Department of Urology and Pathology, Jena University Hospital, Jena, Germany.
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Correlation between genomic alterations assessed by array comparative genomic hybridization, prognostically informative histologic subtype, stage, and patient survival in gastric cancer. Hum Pathol 2011; 42:1937-45. [PMID: 21676433 DOI: 10.1016/j.humpath.2011.02.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Revised: 12/22/2010] [Accepted: 02/16/2011] [Indexed: 02/07/2023]
Abstract
It is difficult to evaluate the prognostic value of histologic criteria in gastric cancer because of the high variability of morphologic patterns. Recently, histologic subtypes of low, intermediate, or high malignant potential have been identified, providing the basis for a prognostically informative grading system. Because array comparative genomic hybridization systems allow systematic analysis of chromosome alterations, which may be prognostically and pathogenetically informative, we applied high-resolution genome-wide array comparative genomic hybridization to archival material from 81 gastric cancer cases followed for a median of 150 months after surgery. The DNA extracted from paraffin sections gave useful results in 49 tumors, 18 of which were of low-grade, 24 of intermediate, and 7 of high-grade histotypes. Based on the number of chromosome aberrations and the presence/absence of amplifications, 3 tumor clusters of increasing genomic lesion severity were constructed, which proved to correlate significantly with histologic grade and stage as well as with patient survival. Further investigation documented the lower number and severity of genomic alterations in tumors with microsatellite DNA instability and high CD8-rich lymphoid response; the close association of 8p23.1 amplification with cardial cancer; the frequent amplification of genes involved in cell renewal (CDC6, HER2, GRB7, IGFBP4) at 17q12-q21.1, with close histochemical correlation with HER2 membranous expression; and more sporadic amplification of chromosome regions harboring important oncogenes like MYC, KRAS, NRAS, CRKL, CCNE1, or ZNF217. We conclude that genome-wide array comparative genomic hybridization of gastric cancer contributes prognostically relevant information providing a genetic background for histologic grading.
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Tabach Y, Kogan-Sakin I, Buganim Y, Solomon H, Goldfinger N, Hovland R, Ke XS, Oyan AM, Kalland KH, Rotter V, Domany E. Amplification of the 20q chromosomal arm occurs early in tumorigenic transformation and may initiate cancer. PLoS One 2011; 6:e14632. [PMID: 21297939 PMCID: PMC3031497 DOI: 10.1371/journal.pone.0014632] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Accepted: 12/03/2010] [Indexed: 11/18/2022] Open
Abstract
Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification.
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Affiliation(s)
- Yuval Tabach
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ira Kogan-Sakin
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Yosef Buganim
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Hilla Solomon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Naomi Goldfinger
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Randi Hovland
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Xi-Song Ke
- The Gade Institute, University of Bergen, Bergen, Norway
- Department of Microbiology, Haukeland University Hospital, Bergen, Norway
| | - Anne M. Oyan
- The Gade Institute, University of Bergen, Bergen, Norway
- Department of Microbiology, Haukeland University Hospital, Bergen, Norway
| | - Karl-H. Kalland
- The Gade Institute, University of Bergen, Bergen, Norway
- Department of Microbiology, Haukeland University Hospital, Bergen, Norway
| | - Varda Rotter
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Eytan Domany
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
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Nobili S, Bruno L, Landini I, Napoli C, Bechi P, Tonelli F, Rubio CA, Mini E, Nesi G. Genomic and genetic alterations influence the progression of gastric cancer. World J Gastroenterol 2011; 17:290-9. [PMID: 21253387 PMCID: PMC3022288 DOI: 10.3748/wjg.v17.i3.290] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Revised: 08/09/2010] [Accepted: 08/16/2010] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer-related deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer. In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.
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Jin Z, Selaru FM, Cheng Y, Kan T, Agarwal R, Mori Y, Olaru AV, Yang J, David S, Hamilton JP, Abraham JM, Harmon J, Duncan M, Montgomery EA, Meltzer SJ. MicroRNA-192 and -215 are upregulated in human gastric cancer in vivo and suppress ALCAM expression in vitro. Oncogene 2010; 30:1577-85. [PMID: 21119604 DOI: 10.1038/onc.2010.534] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The dismal outcome of gastric cancer patients highlights the need for diagnostic biomarkers and effective therapeutic targets, such as microRNAs. We sought to discover microRNAs involved in gastric cancer, and to elucidate their downstream target mechanisms. Both cultured gastric epithelial cells (HFE145 and NCI-N87) and primary human gastric tissues (31 non-neoplastic stomach (NS) and 25 gastric carcinomas (GC)) were studied. MicroRNA microarrays and quantitative RT-PCR were applied to discover and verify differentially expressed microRNAs. in vitro cell migration and invasion, cell proliferation, cell cycle and apoptosis assays were executed to elucidate biological effects of microRNA-192 and -215. Western blotting and luciferase assays were performed to confirm direct messenger RNA targeting by microRNA-192 and -215. MicroRNA microarray analyses revealed that 25 and 20 microRNAs were upregulated and downregulated in GC vs NS, respectively. Expression levels of both microRNA-192 and -215 were significantly higher in GC than in NS (P<0.05). Luciferase assays suggested that microRNA-215 inhibits activated leukocyte cell adhesion molecule (ALCAM) expression at the posttranscriptional level. In addition, expression levels of ALCAM were significantly lower in GC than in NS. Mimics and inhibitors, respectively, of microRNA-192 or -215 exerted no effect on cell cycle or apoptosis in the immortalized normal gastric cell line HFE145 or the gastric cancer cell line NCI-N87. However, mimics of microRNA-192 or -215 significantly increased growth rates in HFE145 cells, whereas inhibitors of microRNA-192 or -215 caused significant decreases in growth rates in NCI-N87 cells. ALCAM knockdown by an ALCAM-specific siRNA significantly increased cell growth in HFE145 cells. Both transfection of mimics of microRNA-192 or -215 and ALCAM knockdown by an ALCAM-specific siRNA significantly increased the migration of HFE145 cells. In conclusion, in gastric cancer, both microRNA-192 and -215 are overexpressed in vivo and exert cell growth and migration-promoting effects in vitro, thus representing potential microRNAs with a role in cancer in the human stomach.
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Affiliation(s)
- Z Jin
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Wang J, Wang Q, Liu H, Hu B, Zhou W, Cheng Y. MicroRNA expression and its implication for the diagnosis and therapeutic strategies of gastric cancer. Cancer Lett 2010; 297:137-43. [PMID: 20797817 DOI: 10.1016/j.canlet.2010.07.018] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 06/28/2010] [Accepted: 07/22/2010] [Indexed: 12/14/2022]
Abstract
MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicated that miRNAs are aberrantly expressed in a variety of human cancers and crucial to tumorigenesis. We herein provide a brief review of miRNA biogenesis, function, deregulation and their possible role as oncogenes or tumor suppressors in the pathogenesis of gastric cancer. The role of miRNAs in the carcinogenic effect of Helicobacter pylori infection was also discussed. Finally, we comment on the potential role of miRNAs in improving the current management of gastric cancer.
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Affiliation(s)
- Jianbo Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, West Wenhua Rd 107, 250012 Jinan, China
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42
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Gümüs-Akay G, Unal AE, Elhan AH, Bayar S, Karadayt K, Sunguroglu A, Kadikiran A, Tükün A. DNA copy number changes in gastric adenocarcinomas: high resolution-comparative genomic hybridization study in Turkey. Arch Med Res 2010; 40:551-60. [PMID: 20082868 DOI: 10.1016/j.arcmed.2009.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2009] [Accepted: 06/25/2009] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIMS Multiple genetic alterations are responsible for development and progression of gastric cancer which is one of the leading causes of cancer-related deaths worldwide. The aim of this study was to identify the genomic imbalances of gains and/or losses in gastric adenocarcinomas from Turkish patients and to investigate their association with development and progression of this type of cancer. METHODS Forty three patients with gastric adenocarcinoma were enrolled in this study and genomic imbalances were analyzed by high-resolution-comparative genomic hybridization (HR-CGH). RESULTS In 36/43 cases (84%) of gastric adenocarcinomas, genomic imbalances have involved all chromosomes in various combinations. The mean number of gains was 3.95+/-4.19 and the most common gains observed were 7q (35%), 8q (35%), 7p (28%), 1q (26%), 13q (26%), and 20q (21%). The calculated mean number of losses was 3.65+/-3.55 and the most common losses were found on arms 18q (26%), 5q (21%), and 14q (21%). High-level amplifications involved chromosomes 1, 7, 8, 9, 13, and 16. No significant differences in chromosomal imbalances were observed in different tumor stages, tumor grades, and Helicobacter pylori infection status groups. The most striking result in this study was the involvement of the 13q gains with increased lymph node metastasis (p=0.046). Late-stage tumors displayed a somewhat significantly higher number of losses than early-stage tumors (p=0.053). CONCLUSIONS A series of gains, losses and amplifications concerned with gastric adenocarcinoma identified in this study are presented in detail. In particular, 13q21-q32 was prominent because it has been linked to increased lymph node metastasis.
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Affiliation(s)
- Güvem Gümüs-Akay
- Department of Medical Biology, Ankara University, Sihhiye, Turkey.
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Junnila S, Kokkola A, Karjalainen-Lindsberg ML, Puolakkainen P, Monni O. Genome-wide gene copy number and expression analysis of primary gastric tumors and gastric cancer cell lines. BMC Cancer 2010; 10:73. [PMID: 20187983 PMCID: PMC2837868 DOI: 10.1186/1471-2407-10-73] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2009] [Accepted: 03/01/2010] [Indexed: 12/26/2022] Open
Abstract
Background Gastric cancer is one of the most common malignancies worldwide and the second most common cause of cancer related death. Gene copy number alterations play an important role in the development of gastric cancer and a change in gene copy number is one of the main mechanisms for a cancer cell to control the expression of potential oncogenes and tumor suppressor genes. Methods To highlight genes of potential biological and clinical relevance in gastric cancer, we carried out a systematic array-based survey of gene expression and copy number levels in primary gastric tumors and gastric cancer cell lines and validated the results using an affinity capture based transcript analysis (TRAC assay) and real-time qRT-PCR. Results Integrated microarray analysis revealed altogether 256 genes that were located in recurrent regions of gains or losses and had at least a 2-fold copy number- associated change in their gene expression. The expression levels of 13 of these genes, ALPK2, ASAP1, CEACAM5, CYP3A4, ENAH, ERBB2, HHIPL2, LTB4R, MMP9, PERLD1, PNMT, PTPRA, and OSMR, were validated in a total of 118 gastric samples using either the qRT-PCR or TRAC assay. All of these 13 genes were differentially expressed between cancerous samples and nonmalignant tissues (p < 0.05) and the association between copy number and gene expression changes was validated for nine (69.2%) of these genes (p < 0.05). Conclusion In conclusion, integrated gene expression and copy number microarray analysis highlighted genes that may be critically important for gastric carcinogenesis. TRAC and qRT-PCR analyses validated the microarray results and therefore the role of these genes as potential biomarkers for gastric cancer.
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Affiliation(s)
- Siina Junnila
- Institute of Biomedicine, Medical Biochemistry and Developmental Biology, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland
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44
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Nakamura Y, Migita T, Hosoda F, Okada N, Gotoh M, Arai Y, Fukushima M, Ohki M, Miyata S, Takeuchi K, Imoto I, Katai H, Yamaguchi T, Inazawa J, Hirohashi S, Ishikawa Y, Shibata T. Krüppel-like factor 12 plays a significant role in poorly differentiated gastric cancer progression. Int J Cancer 2009; 125:1859-67. [PMID: 19588488 DOI: 10.1002/ijc.24538] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Gastric cancer is the second common malignant neoplasia in Japan, and its poorly differentiated form is a deadly disease. To identify novel candidate oncogenes contributing to its genesis, we examined copy-number alterations in 50 primary poorly differentiated gastric cancers using an array-based comparative genomic hybridization (array-CGH). Many genetic changes were identified, including a novel amplification of the 13q22 locus. Several genes are located in this locus, and selective knockdown of one for the Krüppel-like factor 12 (KLF12) induced significant growth-arrest in the HGC27 gastric cancer cell line. Microarray analysis also demonstrated that genes associated with cell proliferation were mostly changed by KLF12 knockdown. To explore the oncogenic function of KLF12, we introduced a full length of human KLF12 cDNA into NIH3T3 and AZ-521 cell lines and found that overexpression significantly enhanced their invasive potential. In clinical samples, KLF12 mRNA in cancer tissue was increased in 11 of 28 cases (39%) when compared with normal gastric epithelium. Clinicopathological analysis further demonstrated a significant correlation between KLF12mRNA levels and tumor size (p = 0.038). These data suggest that the KLF12 gene plays an important role in poorly differentiated gastric cancer progression and is a potential target of therapeutic measures.
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Affiliation(s)
- Yu Nakamura
- Cancer Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan
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Buffart TE, van Grieken NCT, Tijssen M, Coffa J, Ylstra B, Grabsch HI, van de Velde CJH, Carvalho B, Meijer GA. High resolution analysis of DNA copy-number aberrations of chromosomes 8, 13, and 20 in gastric cancers. Virchows Arch 2009; 455:213-23. [PMID: 19697059 PMCID: PMC2744787 DOI: 10.1007/s00428-009-0814-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2009] [Revised: 07/12/2009] [Accepted: 07/16/2009] [Indexed: 02/06/2023]
Abstract
DNA copy-number gains of chromosomes 8q, 13q, and 20q are frequently observed in gastric cancers. Moreover gain of chromosome 20q has been associated with lymph node metastasis. The aim of this study was to correlate DNA copy-number changes of individual genes on chromosomes 8q, 13q, and 20q in gastric adenocarcinomas to clinicopathological data. DNA isolated from 63 formalin-fixed and paraffin-embedded gastric adenocarcinoma tissue samples was analyzed by whole-genome microarray comparative genomic hybridization and by multiplex ligation-dependent probe amplification (MLPA), targeting 58 individual genes on chromosomes 8, 13, and 20. Using array comparative genomic hybridization, gains on 8q, 13q, and 20q were observed in 49 (77.8%), 25 (39.7%), and 49 (77.8%) gastric adenocarcinomas, respectively. Gain of chromosome 20q was significantly correlated with lymph node metastases (p = 0.05) and histological type (p = 0.02). MLPA revealed several genes to be frequently gained in DNA copy number. The oncogene c-myc on 8q was gained in 73% of the cancers, while FOXO1A and ATP7B on 13q were both gained in 28.6% of the cases. Multiple genes on chromosome 20q showed gains in more than 60% of the cancers. DNA copy-number gains of TNFRSF6B (20q13.3) and ZNF217 (20q13.2) were significantly associated with lymph node metastasis (p = 0.02) and histological type (p = 0.02), respectively. In summary, gains of chromosomes 8q, 13q, and 20q in gastric adenocarcinomas harbor DNA copy-number gains of known and putative oncogenes. ZNF217 and TNFRSF6B are associated with important clinicopathological variables, including lymph node status.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, PO Box 7057, 1007, Amsterdam, The Netherlands
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Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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Khayat AS, Guimarães AC, Calcagno DQ, Seabra AD, Lima EM, Leal MF, Faria MHG, Rabenhorst SHB, Assumpção PP, Demachki S, Smith MAC, Burbano RR. Interrelationship between TP53 gene deletion, protein expression and chromosome 17 aneusomy in gastric adenocarcinoma. BMC Gastroenterol 2009; 9:55. [PMID: 19619279 PMCID: PMC2716360 DOI: 10.1186/1471-230x-9-55] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 07/20/2009] [Indexed: 12/14/2022] Open
Abstract
Background This study evaluates the existence of numerical alterations of chromosome 17 and TP53 gene deletion in gastric adenocarcinoma. The p53 protein expression was also evaluated, as well as, possible associations with clinicopathological characteristics. Methods Dual-color fluorescence in situ hybridization and immunostaining were performed in twenty gastric cancer samples of individuals from Northern Brazil. Results Deletion of TP53 was found in all samples. TP53 was inactivated mainly by single allelic deletion, varying to 7–39% of cells/case. Aneusomy of chromosome 17 was observed in 85% of cases. Chromosome 17 monosomy and gain were both observed in about half of cases. Cells with gain of chromosome 17 frequently presented TP53 deletion. The frequency of cells with two chr17 and one TP53 signals observed was higher in diffuse than in intestinal-type GC. Immunoreactivity of p53 was found only in intestinal-type samples. The frequency of cells with two chr17 and two TP53 signals found was higher in samples with positive p53 expression than in negative cases in intestinal-type GC. Conclusion We suggest that TP53 deletion and chromosome 17 aneusomy is a common event in GC and other TP53 alterations, as mutation, may be implicated in the distinct carcinogenesis process of diffuse and intestinal types.
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Affiliation(s)
- André S Khayat
- Human's Cytogenetics Laboratory, Institute of Biological Sciences, Federal University of Pará, Av Augusto Correa 01, 66075-900, Belém, PA, Brazil.
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48
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Hartgrink HH, Jansen EPM, van Grieken NCT, van de Velde CJH. Gastric cancer. LANCET (LONDON, ENGLAND) 2009. [PMID: 19625077 DOI: 10.1016/s0140-6736(09)] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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Buffart TE, Tijssen M, El-Bchiri J, Duval A, van de Wiel MA, Ylstra B, Meijer GA, Carvalho B. NMD inhibition fails to identify tumour suppressor genes in microsatellite stable gastric cancer cell lines. BMC Med Genomics 2009; 2:39. [PMID: 19563644 PMCID: PMC2709900 DOI: 10.1186/1755-8794-2-39] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Accepted: 06/29/2009] [Indexed: 12/05/2022] Open
Abstract
Background Gastric cancers frequently show chromosomal alterations which can cause activation of oncogenes, and/or inactivation of tumour suppressor genes. In gastric cancer several chromosomal regions are described to be frequently lost, but for most of the regions, no tumour suppressor genes have been identified yet. The present study aimed to identify tumour suppressor genes inactivated by nonsense mutation and deletion in gastric cancer by means of GINI (gene identification by nonsense mediated decay inhibition) and whole genome copy number analysis. Methods Two non-commercial gastric cancer cell lines, GP202 and IPA220, were transfected with siRNA directed against UPF1, to specifically inhibit the nonsense mediated decay (NMD) pathway, and with siRNA directed against non-specific siRNA duplexes (CVII) as a control. Microarray expression experiments were performed in triplicate on 4 × 44 K Agilent arrays by hybridizing RNA from UPF1-transfected cells against non-specific CVII-transfected cells. In addition, array CGH of the two cell lines was performed on 4 × 44K agilent arrays to obtain the DNA copy number profiles. Mutation analysis of GINI candidates was performed by sequencing. Results UPF1 expression was reduced for >70% and >80% in the GP202 and IPA220 gastric cancer cell lines, respectively. Integration of array CGH and microarray expression data provided a list of 134 and 50 candidate genes inactivated by nonsense mutation and deletion for GP202 and IPA220, respectively. We selected 12 candidate genes for mutation analysis. Of these, sequence analysis was performed on 11 genes. One gene, PLA2G4A, showed a silent mutation, and in two genes, CTSA and PTPRJ, missense mutations were detected. No nonsense mutations were detected in any of the 11 genes tested. Conclusion Although UPF1 was substantially repressed, thus resulting in the inhibition of the NMD system, we did not find genes inactivated by nonsense mutations. Our results show that the GINI strategy leads to a high number of false positives.
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Affiliation(s)
- Tineke E Buffart
- Dept Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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Suzuki M, Nagura K, Igarashi H, Tao H, Midorikawa Y, Kitayama Y, Sugimura H. Copy number estimation algorithms and fluorescence in situ hybridization to describe copy number alterations in human tumors. Pathol Int 2009; 59:218-228. [PMID: 19351364 DOI: 10.1111/j.1440-1827.2009.02354.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The platforms of high-resolution genetic analysis of human tumors have become popular, and several copy number estimation algorithms have been applied to the data generated by single-nucleotide polymorphism microarrays. Although comparisons have been made between several different platforms or methodologies, there has never been a robust comparison of different copy number estimation algorithms, and the validity of the estimations in comparison with multiple fluorescence in situ hybridization (FISH) data in tumors has rarely been addressed. In the present study the dataset that the Affymetrix 250K Nsp array generated in two cancer cases was used to compare the two widely used algorithms for estimating copy number alterations (CNA): the genotyping microarray-based copy number variation (CNV) analysis (GEMCA) algorithm and the copy number analyzer for Affymetrix Genechip mapping (CNAG) algorithm. Considerable differences were noticed between the estimations by these two algorithms, because of the difference in the formula used to calculate the threshold values. Both algorithms yielded highly consistent data with the FISH results, but CNAG was more stringent for detecting loss. There were areas in which both algorithms provided gains, but FISH showed no change. It will be interesting to pursue the reasons for these remaining discrepancies.
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Affiliation(s)
- Masaya Suzuki
- Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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