|
1
|
Trelford CB, Dagnino L, Di Guglielmo GM. Transforming growth factor-β in tumour development. Front Mol Biosci 2022; 9:991612. [PMID: 36267157 PMCID: PMC9577372 DOI: 10.3389/fmolb.2022.991612] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 09/15/2022] [Indexed: 11/14/2022] Open
Abstract
Transforming growth factor-β (TGFβ) is a ubiquitous cytokine essential for embryonic development and postnatal tissue homeostasis. TGFβ signalling regulates several biological processes including cell growth, proliferation, apoptosis, immune function, and tissue repair following injury. Aberrant TGFβ signalling has been implicated in tumour progression and metastasis. Tumour cells, in conjunction with their microenvironment, may augment tumourigenesis using TGFβ to induce epithelial-mesenchymal transition, angiogenesis, lymphangiogenesis, immune suppression, and autophagy. Therapies that target TGFβ synthesis, TGFβ-TGFβ receptor complexes or TGFβ receptor kinase activity have proven successful in tissue culture and in animal models, yet, due to limited understanding of TGFβ biology, the outcomes of clinical trials are poor. Here, we review TGFβ signalling pathways, the biology of TGFβ during tumourigenesis, and how protein quality control pathways contribute to the tumour-promoting outcomes of TGFβ signalling.
Collapse
Affiliation(s)
- Charles B. Trelford
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Lina Dagnino
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Oncology, Children’s Health Research Institute and Lawson Health Research Institute, London, ON, Canada
| | - Gianni M. Di Guglielmo
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| |
Collapse
|
|
2
|
Identification of a Genomic Instability-Related Long Noncoding RNA Prognostic Model in Colorectal Cancer Based on Bioinformatic Analysis. DISEASE MARKERS 2022; 2022:4556585. [PMID: 35711569 PMCID: PMC9197617 DOI: 10.1155/2022/4556585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/17/2022] [Indexed: 11/17/2022]
Abstract
Background. In recent years, a growing body of research has revealed that long noncoding RNAs (lncRNAs) participate in regulating genomic instability. Materials and Methods. We obtained RNA expression profiles, somatic mutation profiles, clinical information, and pathological features of colorectal cancer (CRC) from The Cancer Genome Atlas project. We divided the cohort into two groups based on mutation frequency and identified genomic instability-related lncRNAs (GI-lncRNAs) using R software. We further analyzed the function of identified GI-lncRNAs and established a prognostic model through Cox regression. Using the established prognostic model, we divided the cohort into the high- and low-risk groups and further verified the prognostic differences between the two groups as well as the predictive power of prognosis-related lncRNAs in the genomic instability of CRC. Results. We identified a total of 143 GI-lncRNAs that were differentially expressed between the higher mutation frequency group and the lower mutation frequency group. According to Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses, a series of cancer-associated terms were enriched. We further constructed a prognostic model that included five GI-lncRNAs (lncRNA PTPRD-AS1, lncRNA AC009237.14, lncRNA LINC00543, lncRNA AP003555.1, and lncRNA AL109615.3). We confirmed that the expression of the five GI-lncRNAs was associated with prognosis and the mutation of critical genes in the CRC patient cohort. Conclusions. The present research further confirmed the vital function of GI-lncRNAs in the genomic instability of CRC. The five GI-lncRNAs identified in our study are potential biomarkers and need to be studied in more depth.
Collapse
|
|
3
|
Stanilov N, Grigorova A, Velikova T, Stanilova SA. Genetic variation of TGF-ΒR2 as a protective genotype for the development of colorectal cancer in men. World J Gastrointest Oncol 2021; 13:1766-1780. [PMID: 34853649 PMCID: PMC8603459 DOI: 10.4251/wjgo.v13.i11.1766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/19/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of transforming growth factor beta (TGF-β) signaling, including both the cytokine and their receptors, in the etiology of colorectal cancer (CRC) has been of particular interest lately. AIM To investigate the association between promoter polymorphism in TGF-β receptor 2 TGF-ΒR2G[-875]A with a CRC risk in a cohort of Bulgarian patients using a case-control gene association study approach, as well as the protein levels of TGF-β1 in the peripheral blood. METHODS A cohort of 184 CRC patients and 307 sex and age-matched healthy subjects were recruited in the study. A genotyping of the TGF-ΒR2G[-875]A (rs3087465) polymorphism was performed by primer-introduced restriction analyses-polymerase chain reaction approaches. RESULTS The frequency of TGF-ΒR2G[-875]A genotype was decreased in male patients with CRC than in healthy men (31.3% vs 44.8%; P = 0.058). Among males, the TGF-ΒR2G[-509]G genotype was related to a significantly increased risk of CRC development (OR = 1.820, 95%CI: 0.985-3.362, P = 0.055) than the GA + AA genotype. Also, TGF-ΒR2[-875]*A-allele itself was rarer in men with CRC than healthy men (19.1% vs 26.9%, P = 0.086) and was associated with a protective effect (OR = 0.644; 95%CI: 0.389-1.066; P = 0.086). Regarding the genotypes, we found that TGF-β1 serum levels were higher in GG genotype in healthy persons above 50 years than the CRC patients [36.3 ng/mL interquartile range (IQR) 19.9-56.5 vs 22.4 ng/mL IQR 14.8-29.7, P = 0.014]. We found significant differences between higher levels of TGF-β1 serum levels in healthy controls above 50 years (GG genotype) and CRC patients (GG genotype) at the early stage (36.3 ng/mL IQR 19.9-56.5 vs 22.8 ng/mL IQR 14.6-28.6, P = 0.037) and advanced CRC (36.3 ng/mL IQR 19.9-56.5 vs 21.6 ng/mL IQR 15.9-33.9, P = 0.039). CONCLUSION In summary, our results demonstrated that TGF-ΒR2 AG and AA genotypes were associated with a reduced risk of CRC, as well as circulating levels of TGF-β could prevent CRC development in a gender-specific manner. Notably, male carriers of TGF-ΒR2 -875A allele genotypes had a lower risk of CRC development and progression, suggesting that TGF-ΒR2 -875A/G polymorphism significantly affects the protective biological factors that also impact the risk of colon and rectal carcinogenesis.
Collapse
Affiliation(s)
- Noyko Stanilov
- Oncoplastic Unit, University College London Hospital, London NW1 2BU, United Kingdom
| | - Antonia Grigorova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Spaska Angelova Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
| |
Collapse
|
|
4
|
Bi C, Cui H, Fan H, Li L. LncRNA LINC01116 Promotes the Development of Colorectal Cancer by Targeting miR-9-5p/STMN1. Onco Targets Ther 2020; 13:10547-10558. [PMID: 33116633 PMCID: PMC7573327 DOI: 10.2147/ott.s253532] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 07/07/2020] [Indexed: 12/18/2022] Open
Abstract
PURPOSE The aim was to research the role of LINC01116 in the prognosis of colorectal cancer (CRC) patients and development of colorectal cancer cells. METHODS In total 62 colorectal cancer patient tissues and human CRC cell lines (OUMS23, SW116, SW480 and LOVO) were obtained for this study. SiLINC01116, miR-9-5p mimic, LINC01116, oe-STMN1 and their controls were transfected. The qRT-PCR method and Western blot were used to detect the levels of LINC01116, miR-9-5p and STMN1 in tissues and cells. CCK8 assay and flow cytometry were processed for proliferation and apoptosis, respectively. Transwell assay was undertaken to verify invasion and migration. Luciferase assay and pull down assay were processed to confirm the binding relationship among LINC01116, miR-9-5p and STMN1. Immunohistochemistry assay also detected the expression of STMN1. Kaplan-Meier survival curve was used to analyze patient survival rate. Pearson correlation analysis was used to evaluate the regulatory relationship between LINC01116, miR-9-5p and STMN1 in tissues. RESULTS LINC01116 was expressed higher in CRC tissues and cells. Patients with higher expression of LINC01116 had worse prognosis. Knockdown of LINC01116 suppressed development of CRC cell. LINC01116 negatively regulated miR-9-5p, while MiR-9-5p was negatively related to STMN1. miR-9-5p mimic could rescue the effect of LINC01116, inhibit migration and invasion, and improve apoptosis of CRC cells. Oe-STMN1 could also rescue the effect of miR-9-5p on the development of colorectal cancer. CONCLUSION LINC01116 promoted the development of colorectal cancer via modulating miR-9-5p/STMN1 axis.
Collapse
Affiliation(s)
- Chongyao Bi
- Department of General Surgery, Jiaozhou Central Hospital of Qingdao, Qingdao266300, People’s Republic of China
| | - Hongshuai Cui
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao266041, People’s Republic of China
| | - Haijing Fan
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao266041, People’s Republic of China
| | - Lai Li
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao266041, People’s Republic of China
| |
Collapse
|
|
5
|
Razzaque MS, Atfi A. TGIF1-Twist1 axis in pancreatic ductal adenocarcinoma. Comput Struct Biotechnol J 2020; 18:2568-2572. [PMID: 33005315 PMCID: PMC7520386 DOI: 10.1016/j.csbj.2020.09.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/18/2022] Open
Abstract
TG-interacting factor 1 (TGIF1) exerts inhibitory effects on transforming growth factor-beta (TGF-β) signaling by suppressing Smad signaling pathway at multiple levels. TGIF1 activity is important for normal embryogenesis and organogenesis, yet its dysregulation can culminate in tumorigenesis. For instance, increased expression of TGIF1 correlates with poor prognosis in triple-negative breast cancer patients, and enforced expression of TGIF1 facilitates Wnt-driven mammary tumorigenesis, suggesting that TGIF1 might function as an oncoprotein. Quite surprisingly, TGIF1 has recently been shown to function as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC), possibly owing to its ability to antagonize the pro-malignant transcription factor Twist1. In this article, we will briefly elaborate on the biological and clinical significance of the unique tumor-suppressive function of TGIF1 and its functional interaction with Twist1 in the context of PDAC pathogenesis and progression.
Collapse
Affiliation(s)
- Mohammed S Razzaque
- Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
| | - Azeddine Atfi
- Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| |
Collapse
|
|
6
|
He H, Zhao X, Zhu Z, Du L, Chen E, Liu S, Li Q, Dong J, Yang J, Lei L. MicroRNA-3191 promotes migration and invasion by downregulating TGFBR2 in colorectal cancer. J Biochem Mol Toxicol 2019; 33:e22308. [PMID: 30770602 DOI: 10.1002/jbt.22308] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/16/2019] [Accepted: 02/05/2019] [Indexed: 12/11/2022]
Abstract
Mutations in transforming growth factor beta receptor II (TGFBR2) are detected in up to 30% of overall colorectal cancer (CRC). Dysregulation of some microRNAs participated in the CRC pathogenesis. In this study, we used the gene ontology analyses, the Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene set enrichment analysis to indicate that miR-3191 was involved in the regulation of transforming growth factor beta (TGF-BETA) signal pathway in CRC. These bioinformatics results were supported by data obtained from CRC samples and experiments in vitro. The luciferase reporter assay was used to confirm that miR-3191 modulates TGF-BETA signal pathway by targeting TGFBR2. By transwell migration and invasion assays, we showed that miR-3191 promoted CRC cell migration and invasion by downregulating TGFBR2. And it may serve as a novel therapeutic strategy for treating CRC patients.
Collapse
Affiliation(s)
- Hongjuan He
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Xiaojuan Zhao
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Ziqing Zhu
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Le Du
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Shuzhen Liu
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Qiqi Li
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Jing Dong
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Jin Yang
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| | - Lei Lei
- Key Laboratory of Resource Biology and Biotechnology, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Northwest University, Xi'an, China
| |
Collapse
|
|
7
|
Fadaka AO, Pretorius A, Klein A. Biomarkers for Stratification in Colorectal Cancer: MicroRNAs. Cancer Control 2019; 26:1073274819862784. [PMID: 31431043 PMCID: PMC6704426 DOI: 10.1177/1073274819862784] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 06/08/2019] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. In spite of the fact that the death rates have declined over the previous decade, particularly because of enhanced screening or potential treatment alternatives, CRC still remains the third leading cause of cancer-related mortality in the world, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Unlike prostate and lung cancer, CRC is not easily detectable in its early stage, which may also account for its high mortality rate. MicroRNAs (miRNAs) are a class of noncoding RNAs. The roles of these noncoding RNAs have been implicated in cancer pathogenesis, most especially CRC, due to their ability to posttranscriptionally regulate the expression of oncogenes and tumor suppressor genes. Dysregulated expression of many miRNAs regulates the expression of hundreds of growth regulatory genes and pathways that are important in the multistep model of colorectal carcinogenesis. If CRC is detected early, it is a largely treatable disease. Early diagnosis, including the identification of premalignant adenomas, is regarded a major concept for improving patient survival in CRC treatment. Several lines of research suggest that miRNAs are closely implicated in the metastatic process in CRC and some of these miRNAs could be useful as promising clinical tools for identifying specific stages of CRC due to their differential expression. This review discusses the correlation between CRC staging relative to the specific expression of miRNA for early detection, treatment, and disease management.
Collapse
Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| | - Ashley Pretorius
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| | - Ashwil Klein
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| |
Collapse
|
|
8
|
Kim SY, Kim TI. Serrated neoplasia pathway as an alternative route of colorectal cancer carcinogenesis. Intest Res 2018; 16:358-365. [PMID: 30090034 PMCID: PMC6077295 DOI: 10.5217/ir.2018.16.3.358] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 01/10/2023] Open
Abstract
In the past two decades, besides conventional adenoma pathway, a subset of colonic lesions, including hyperplastic polyps, sessile serrated adenoma/polyps, and traditional serrated adenomas have been suggested as precancerous lesions via the alternative serrated neoplasia pathway. Major molecular alterations of sessile serrated neoplasia include BRAF mutation, high CpG island methylator phenotype, and escape of cellular senescence and progression via methylation of tumor suppressor genes or mismatch repair genes. With increasing information of the morphologic and molecular features of serrated lesions, one major challenge is how to reflect this knowledge in clinical practice, such as pathologic and endoscopic diagnosis, and guidelines for treatment and surveillance.
Collapse
Affiliation(s)
- Soon Young Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
9
|
Seoane J, Gomis RR. TGF-β Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harb Perspect Biol 2017; 9:cshperspect.a022277. [PMID: 28246180 DOI: 10.1101/cshperspect.a022277] [Citation(s) in RCA: 372] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Transforming growth factor-β (TGF-β) induces a pleiotropic pathway that is modulated by the cellular context and its integration with other signaling pathways. In cancer, the pleiotropic reaction to TGF-β leads to a diverse and varied set of gene responses that range from cytostatic and apoptotic tumor-suppressive ones in early stage tumors, to proliferative, invasive, angiogenic, and oncogenic ones in advanced cancer. Here, we review the knowledge accumulated about the molecular mechanisms involved in the dual response to TGF-β in cancer, and how tumor cells evolve to evade the tumor-suppressive responses of this signaling pathway and then hijack the signal, converting it into an oncogenic factor. Only through the detailed study of this complexity can the suitability of the TGF-β pathway as a therapeutic target against cancer be evaluated.
Collapse
Affiliation(s)
- Joan Seoane
- Translational Research Program, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Roger R Gomis
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.,Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| |
Collapse
|
|
10
|
Abstract
Transforming growth factor βs (TGF-βs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-β type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-β ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-β signaling for therapeutic benefit. This review will cover the basics of TGF-β signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-β blockade strategies, and give an update on preclinical and clinical trials for TGF-β blockade in a variety of solid tumor types.
Collapse
Affiliation(s)
- Rosemary J Akhurst
- Department of Anatomy and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94158-9001
| |
Collapse
|
|
11
|
Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, Hillemanns P, Preus L, Knutson KL, Wallace PK, Hong CC, Friel G, Davis W, Nesline M, Pearce CL, Kelemen LE, Goodman MT, Bandera EV, Terry KL, Schoof N, Eng KH, Clay A, Singh PK, Joseph JM, Aben KK, Anton-Culver H, Antonenkova N, Baker H, Bean Y, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Cook LS, Cramer DW, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Despierre E, Dicks E, Doherty JA, du Bois A, Dürst M, Easton D, Eccles D, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Gronwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hogdall C, Hogdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Karlan BY, Kellar M, Kelley JL, Kiemeney LA, Klapdor R, Kolomeyevskaya N, Krakstad C, Kjaer SK, Kruszka B, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Liu S, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, et alHampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, Hillemanns P, Preus L, Knutson KL, Wallace PK, Hong CC, Friel G, Davis W, Nesline M, Pearce CL, Kelemen LE, Goodman MT, Bandera EV, Terry KL, Schoof N, Eng KH, Clay A, Singh PK, Joseph JM, Aben KK, Anton-Culver H, Antonenkova N, Baker H, Bean Y, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Cook LS, Cramer DW, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Despierre E, Dicks E, Doherty JA, du Bois A, Dürst M, Easton D, Eccles D, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Gronwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hogdall C, Hogdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Karlan BY, Kellar M, Kelley JL, Kiemeney LA, Klapdor R, Kolomeyevskaya N, Krakstad C, Kjaer SK, Kruszka B, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Liu S, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Moes-Sosnowska J, Narod SA, Nedergaard L, Nevanlinna H, Nickels S, Olson SH, Orlow I, Weber RP, Paul J, Pejovic T, Pelttari LM, Perkins B, Permuth-Wey J, Pike MC, Plisiecka-Halasa J, Poole EM, Risch HA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schernhammer E, Schmitt K, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Tangen IL, Teo SH, Thompson PJ, Timorek A, Tsai YY, Tworoger SS, Tyrer J, van Altena AM, Vergote I, Vierkant RA, Walsh C, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Woo YL, Yang H, Zheng W, Ziogas A, Gayther SA, Ramus SJ, Sellers TA, Schildkraut JM, Phelan CM, Berchuck A, Chenevix-Trench G, Cunningham JM, Pharoah PP, Ness RB, Odunsi K, Goode EL, Moysich KB. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer. Oncotarget 2016; 7:69097-69110. [PMID: 27533245 PMCID: PMC5340115 DOI: 10.18632/oncotarget.10215] [Show More Authors] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 12/31/1969] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
Collapse
MESH Headings
- Adenocarcinoma, Clear Cell/genetics
- Adenocarcinoma, Clear Cell/immunology
- Adult
- Aged
- Carcinoma, Ovarian Epithelial
- Female
- Gene Expression Regulation, Neoplastic
- Gene Frequency
- Genetic Predisposition to Disease/genetics
- Genotype
- Humans
- Middle Aged
- Neoplasms, Glandular and Epithelial/genetics
- Neoplasms, Glandular and Epithelial/immunology
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/immunology
- Polymorphism, Single Nucleotide
- Protein Serine-Threonine Kinases/genetics
- Receptor, Transforming Growth Factor-beta Type II
- Receptors, Transforming Growth Factor beta/genetics
- Risk Factors
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
Collapse
Affiliation(s)
- Shalaka S. Hampras
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Lara E. Sucheston-Campbell
- College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Rikki Cannioto
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Jenny Chang-Claude
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Francesmary Modugno
- Department of Epidemiology and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Peter Hillemanns
- Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
| | - Leah Preus
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Keith L. Knutson
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
| | - Paul K. Wallace
- Department of Flow & Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Chi-Chen Hong
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Grace Friel
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Warren Davis
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Mary Nesline
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Celeste L. Pearce
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Linda E. Kelemen
- Alberta Health Services-Cancer Care, Department of Population Health Research, Calgary, Alberta, Canada
| | - Marc T. Goodman
- Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Elisa V. Bandera
- Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Kathryn L. Terry
- Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Nils Schoof
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kevin H. Eng
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Alyssa Clay
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Prashant K. Singh
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Janine M. Joseph
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Katja K.H. Aben
- Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Hoda Anton-Culver
- Department of Epidemiology and School of Medicine, University of California Irvine, Irvine, California, USA
| | - Natalia Antonenkova
- Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus
| | - Helen Baker
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Yukie Bean
- Department of Obstetrics & Gynecology and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Matthias W. Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Maria Bisogna
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Line Bjorge
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Natalia Bogdanova
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Louise A. Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Angela Brooks-Wilson
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
| | - Fiona Bruinsma
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
| | - Ralf Butzow
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Ian G. Campbell
- Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia
| | - Karen Carty
- Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
| | - Linda S. Cook
- Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA
| | - Daniel W. Cramer
- Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Cezary Cybulski
- International Hereditary Cancer Center, Department of Genetics and Pathology, Clinic of Opthalmology, Pomeranian Medical University, Szczecin, Poland
| | - Agnieszka Dansonka-Mieszkowska
- Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Joe Dennis
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Evelyn Despierre
- Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium
| | - Ed Dicks
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Jennifer A. Doherty
- Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Andreas du Bois
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
| | - Matthias Dürst
- Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
| | - Doug Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Diana Eccles
- Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
| | - Robert P. Edwards
- Department of Obstetrics, Gynecology & Reproductive Sciences and Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Arif B. Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Peter A. Fasching
- Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA
| | - Brooke L. Fridley
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | | | - Aleksandra Gentry-Maharaj
- Institute for Women's Health, Population Health Sciences, University College - London, London, United Kingdom
| | - Graham G. Giles
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Rosalind Glasspool
- Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
| | - Jacek Gronwald
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Patricia Harrington
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Philipp Harter
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
| | - Hanis Nazihah Hasmad
- Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia
| | - Alexander Hein
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Florian Heitz
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
| | | | - Claus Hogdall
- Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Estrid Hogdall
- Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
| | - Satoyo Hosono
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Edwin S. Iversen
- Department of Statistical Science, Duke University, Durham, North Carolina, USA
| | - Anna Jakubowska
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Allan Jensen
- Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Bu-Tian Ji
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Beth Y. Karlan
- Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Melissa Kellar
- Department of Obstetrics & Gynecology and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Joseph L. Kelley
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Lambertus A. Kiemeney
- Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Rüdiger Klapdor
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Nonna Kolomeyevskaya
- Division of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Camilla Krakstad
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Susanne K. Kjaer
- Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Bridget Kruszka
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Jolanta Kupryjanczyk
- Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium
| | - Sandrina Lambrechts
- Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium
| | - Nhu D. Le
- Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada
| | - Alice W. Lee
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Shashikant Lele
- Division of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Arto Leminen
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Jenny Lester
- Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Douglas A. Levine
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dong Liang
- College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
| | - Jolanta Lissowska
- Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Song Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Karen Lu
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jan Lubinski
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Lene Lundvall
- Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Leon F.A.G. Massuger
- Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Keitaro Matsuo
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Valeria McGuire
- Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA
| | - John R. McLaughlin
- Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Ian McNeish
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Usha Menon
- Women's Cancer, UCL EGA Institute for Women's Health, London, UK
| | - Joanna Moes-Sosnowska
- Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Steven A. Narod
- Women's College Research Institute, Toronto, Ontario, Canada
| | - Lotte Nedergaard
- Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark
| | - Heli Nevanlinna
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Stefan Nickels
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Sara H. Olson
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Irene Orlow
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Rachel Palmieri Weber
- Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - James Paul
- Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
| | - Tanja Pejovic
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Liisa M. Pelttari
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Barbara Perkins
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Jenny Permuth-Wey
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Malcolm C. Pike
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Joanna Plisiecka-Halasa
- Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Elizabeth M. Poole
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Mary Anne Rossing
- Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Joseph H. Rothstein
- Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA
| | - Anja Rudolph
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Ingo B. Runnebaum
- Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
| | - Iwona K. Rzepecka
- Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Helga B. Salvesen
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Eva Schernhammer
- Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Kristina Schmitt
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Ira Schwaab
- Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
| | - Xiao-Ou Shu
- Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Yurii B Shvetsov
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA
| | - Nadeem Siddiqui
- Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, Scotland, UK
| | - Weiva Sieh
- Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA
| | - Honglin Song
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Melissa C. Southey
- Department of Pathology, The University of Melbourne, Melbourne, Australia
| | - Ingvild L. Tangen
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Soo-Hwang Teo
- Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia
| | - Pamela J. Thompson
- Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Agnieszka Timorek
- Department of Obstetrics, Gynecology and Oncology, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland
| | - Ya-Yu Tsai
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Shelley S. Tworoger
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan Tyrer
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Anna M. van Altena
- Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Ignace Vergote
- Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium
| | - Robert A. Vierkant
- Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Christine Walsh
- Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Shan Wang-Gohrke
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Alice S. Whittemore
- Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA
| | - Kristine G. Wicklund
- Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Lynne R. Wilkens
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA
| | - Anna H. Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yin-Ling Woo
- Department of Obstetrics and Gynaecology, Affiliated with UM Cancer Research Institute, Faculty of Medicine, University of Malaya, Malaysia
| | - Hannah Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Wei Zheng
- Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Argyrios Ziogas
- Department of Epidemiology and School of Medicine, University of California Irvine, Irvine, California, USA
| | - Simon A. Gayther
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Susan J. Ramus
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Thomas A. Sellers
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Joellen M. Schildkraut
- Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Catherine M. Phelan
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Andrew Berchuck
- Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA
| | - Georgia Chenevix-Trench
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- On behalf of the Australian Ovarian Cancer Study Group
| | - Julie M. Cunningham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Paul P. Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Roberta B. Ness
- School of Public Health, The University of Texas, Houston, Texas, USA
| | - Kunle Odunsi
- Division of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Ellen L. Goode
- Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kirsten B. Moysich
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
| |
Collapse
|
|
12
|
Li J, Liang H, Bai M, Ning T, Wang C, Fan Q, Wang Y, Fu Z, Wang N, Liu R, Zen K, Zhang CY, Chen X, Ba Y. miR-135b Promotes Cancer Progression by Targeting Transforming Growth Factor Beta Receptor II (TGFBR2) in Colorectal Cancer. PLoS One 2015; 10:e0130194. [PMID: 26061281 PMCID: PMC4462589 DOI: 10.1371/journal.pone.0130194] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 05/16/2015] [Indexed: 01/01/2023] Open
Abstract
The transforming growth factor beta (TGF-β) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colorectal cancer (CRC). The inactivation of TGFBR2 is the most common genetic event affecting the TGF-β signaling pathway. However, the mechanism by which cancer cells downregulate TGFBR2 is unclear. In this study, we found that the TGFBR2 protein levels were consistently upregulated in CRC tissues, whereas its mRNA levels varied in these tissues, suggesting that a post-transcriptional mechanism is involved in the regulation of TGFBR2. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that potentially target TGFBR2. We identified the specific targeting site of miR-135b in the 3'-untranslated region (3'-UTR) of TGFBR2. We further identified an inverse correlation between the levels of miR-135b and TGFBR2 protein, but not mRNA, in CRC tissue samples. By overexpressing or silencing miR-135b in CRC cells, we experimentally validated that miR-135b directly binds to the 3'-UTR of the TGFBR2 transcript and regulates TGFBR2 expression. Furthermore, the biological consequences of the targeting of TGFBR2 by miR-135b were examined using in vitro cell proliferation and apoptosis assays. We demonstrated that miR-135b exerted a tumor-promoting effect by inducing the proliferation and inhibiting the apoptosis of CRC cells via the negative regulation of TGFBR2 expression. Taken together, our findings provide the first evidence supporting the role of miR-135b as an oncogene in CRC via the inhibition of TGFBR2 translation.
Collapse
Affiliation(s)
- Jialu Li
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tiyuanbei, Tianjin, 300060, China
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Hongwei Liang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Ming Bai
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tiyuanbei, Tianjin, 300060, China
| | - Tao Ning
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tiyuanbei, Tianjin, 300060, China
| | - Cheng Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
- Department of Clinical Laboratory, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, China
| | - Qian Fan
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tiyuanbei, Tianjin, 300060, China
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Yanbo Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Zheng Fu
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Nan Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Rui Liu
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tiyuanbei, Tianjin, 300060, China
| | - Ke Zen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Chen-Yu Zhang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Xi Chen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Yi Ba
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| |
Collapse
|
|
13
|
Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, de Gramont A. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther 2014; 147:22-31. [PMID: 25444759 DOI: 10.1016/j.pharmthera.2014.11.001] [Citation(s) in RCA: 491] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 09/25/2014] [Indexed: 02/07/2023]
Abstract
The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings.
Collapse
Affiliation(s)
- Cindy Neuzillet
- INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | | | - Romain Cohen
- AAREC Filia Research, Translational Department, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France
| | - Jérôme Cros
- Department of Pathology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Sandrine Faivre
- INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Eric Raymond
- New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland
| | - Armand de Gramont
- New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland.
| |
Collapse
|
|
14
|
Bathe OF, Farshidfar F. From genotype to functional phenotype: unraveling the metabolomic features of colorectal cancer. Genes (Basel) 2014; 5:536-60. [PMID: 25055199 PMCID: PMC4198916 DOI: 10.3390/genes5030536] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 05/27/2014] [Accepted: 06/27/2014] [Indexed: 12/12/2022] Open
Abstract
Much effort in recent years has been expended in defining the genomic and epigenetic alterations that characterize colorectal adenocarcinoma and its subtypes. However, little is known about the functional ramifications related to various subtypes. Metabolomics, the study of small molecule intermediates in disease, provides a snapshot of the functional phenotype of colorectal cancer. Data, thus far, have characterized some of the metabolic perturbations that accompany colorectal cancer. However, further studies will be required to identify biologically meaningful metabolic subsets, including those corresponding to specific genetic aberrations. Moreover, further studies are necessary to distinguish changes due to tumor and the host response to tumor.
Collapse
Affiliation(s)
- Oliver F Bathe
- Department of Surgery, Tom Baker Cancer Center, University of Calgary, 1331 29th St NW, Calgary, AB T2N 4N2, Canada.
| | - Farshad Farshidfar
- Department of Surgery, Tom Baker Cancer Center, University of Calgary, 1331 29th St NW, Calgary, AB T2N 4N2, Canada.
| |
Collapse
|
|
15
|
Hsieh WJ, Lin FM, Huang HD, Wang H. Investigating microRNA-target interaction-supported tissues in human cancer tissues based on miRNA and target gene expression profiling. PLoS One 2014; 9:e95697. [PMID: 24756070 PMCID: PMC3995724 DOI: 10.1371/journal.pone.0095697] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 03/28/2014] [Indexed: 01/12/2023] Open
Abstract
UNLABELLED Recent studies have revealed that a small non-coding RNA, microRNA (miRNA) down-regulates its mRNA targets. This effect is regarded as an important role in various biological processes. Many studies have been devoted to predicting miRNA-target interactions. These studies indicate that the interactions may only be functional in some specific tissues, which depend on the characteristics of an miRNA. No systematic methods have been established in the literature to investigate the correlation between miRNA-target interactions and tissue specificity through microarray data. In this study, we propose a method to investigate miRNA-target interaction-supported tissues, which is based on experimentally validated miRNA-target interactions. The tissue specificity results by our method are in accordance with the experimental results in the literature. AVAILABILITY AND IMPLEMENTATION Our analysis results are available at http://tsmti.mbc.nctu.edu.tw/ and http://www.stat.nctu.edu.tw/hwang/tsmti.html.
Collapse
Affiliation(s)
- Wan J. Hsieh
- Institute of Statistics, National Chiao Tung University, Hsinchu, Taiwan
| | - Feng-Mao Lin
- Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan
| | - Hsien-Da Huang
- Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan
- * E-mail: (HW); (H-DH)
| | - Hsiuying Wang
- Institute of Statistics, National Chiao Tung University, Hsinchu, Taiwan
- * E-mail: (HW); (H-DH)
| |
Collapse
|
|
16
|
Lyu X, Fang W, Cai L, Zheng H, Ye Y, Zhang L, li J, Peng H, Cho WCS, Wang E, Marincola FM, Yao K, Cai H, Li J, Li X. TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness. Mol Cancer 2014; 13:51. [PMID: 24606633 PMCID: PMC4016586 DOI: 10.1186/1476-4598-13-51] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 03/01/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown. METHODS We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation. RESULTS TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC. CONCLUSION The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.
Collapse
Affiliation(s)
- Xiaoming Lyu
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| | - Weiyi Fang
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| | - Longmei Cai
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| | - Hang Zheng
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
- Departments of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanfen Ye
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| | - Lan Zhang
- Department of Otorhinolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinbang li
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| | - Hong Peng
- Department of Otorhinolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Guangzhou, Hong Kong
| | - Ena Wang
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | - Francesco M Marincola
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | - Kaitai Yao
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| | - Hongbing Cai
- School of Chinese Traditional Medicine, Southern Medical University, Guangzhou, China
| | - Jiliang Li
- School of Biotechnology, Southern Medical University, Guangzhou, China
- Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Xin Li
- Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
17
|
Sweetser S, Smyrk TC, Sinicrope FA. Serrated colon polyps as precursors to colorectal cancer. Clin Gastroenterol Hepatol 2013; 11:760-7; quiz e54-5. [PMID: 23267866 PMCID: PMC3628288 DOI: 10.1016/j.cgh.2012.12.004] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 11/27/2012] [Accepted: 12/07/2012] [Indexed: 02/07/2023]
Abstract
Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights include an increased recognition of the malignant potential of different types of serrated polyps such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors that have microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. These data have important implications for clinical practice and CRC prevention, because hyperplastic polyps were previously regarded as having no malignant potential. There is also evidence that the serrated pathway contributes to interval or missed cancers. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps to facilitate their detection and removal, and thereby ensure a high-quality colonoscopic examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in postpolypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence.
Collapse
Affiliation(s)
- Seth Sweetser
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Thomas C. Smyrk
- Division of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, MN
| | - Frank A. Sinicrope
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
- Division of Oncology, Mayo Clinic College of Medicine, Rochester, MN
| |
Collapse
|
|
18
|
Choi YM, Shim KS, Yoon KL, Han MY, Cha SH, Kim SK, Jung JH. Transforming growth factor beta receptor II polymorphisms are associated with Kawasaki disease. KOREAN JOURNAL OF PEDIATRICS 2012; 55:18-23. [PMID: 22359526 PMCID: PMC3282214 DOI: 10.3345/kjp.2012.55.1.18] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 09/27/2011] [Accepted: 11/12/2011] [Indexed: 12/12/2022]
Abstract
Purpose Transforming growth factor beta receptor 2 (TGFBR2) is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs) of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of TGFBR2 gene suggest that the TGFBR2 gene SNPs are related to the pathogenesis of Kawasaki disease (KD) and coronary artery lesion (CAL). Methods The subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected TGFBR2 gene SNPs from serum and performed direct sequencing. Results The sequences of the eleven SNPs in the TGFBR2 gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430) were associated with development of KD (P=0.019, P=0.026, P=0.016, respectively). One SNP (rs1495592) was associated with CAL in KD group (P=0.022). Conclusion Eleven SNPs in TGFBR2 gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the TGFBR2 gene. One of the six SNPs (rs6550004) was associated with development of KD. One SNP associated with CAL (rs1495592) was disassociated from the TGFBR2 gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.
Collapse
Affiliation(s)
- Yu Mi Choi
- Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Chapnick DA, Warner L, Bernet J, Rao T, Liu X. Partners in crime: the TGFβ and MAPK pathways in cancer progression. Cell Biosci 2011; 1:42. [PMID: 22204556 PMCID: PMC3275500 DOI: 10.1186/2045-3701-1-42] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 12/28/2011] [Indexed: 12/27/2022] Open
Abstract
The TGFβ and Ras-MAPK pathways play critical roles in cell development and cell cycle regulation, as well as in tumor formation and metastasis. In the absence of cellular transformation, these pathways operate in opposition to one another, where TGFβ maintains an undifferentiated cell state and suppresses proliferation, while Ras-MAPK pathways promote proliferation, survival and differentiation. However, in colorectal and pancreatic cancers, the opposing pathways' mechanisms are simultaneously activated in order to promote cancer progression and metastasis. Here, we highlight the roles of the TGFβ and Ras-MAPK pathways in normal and malignant states, and provide an explanation for how the concomitant activation of these pathways drives tumor biology. Finally, we survey potential therapeutic targets in these pathways.
Collapse
Affiliation(s)
- Douglas A Chapnick
- Department of Chemistry and Biochemistry and Molecular, Cellular and Developmental Biology
| | - Lisa Warner
- Department of Chemistry and Biochemistry and Molecular, Cellular and Developmental Biology
| | | | - Timsi Rao
- Department of Chemistry and Biochemistry and Molecular, Cellular and Developmental Biology
| | - Xuedong Liu
- Department of Chemistry and Biochemistry and Molecular, Cellular and Developmental Biology
| |
Collapse
|
|
20
|
TGFBR2 and BAX mononucleotide tract mutations, microsatellite instability, and prognosis in 1072 colorectal cancers. PLoS One 2011; 6:e25062. [PMID: 21949851 PMCID: PMC3176811 DOI: 10.1371/journal.pone.0025062] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2011] [Accepted: 08/25/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mononucleotide tracts in the coding regions of the TGFBR2 and BAX genes are commonly mutated in microsatellite instability-high (MSI-high) colon cancers. The receptor TGFBR2 plays an important role in the TGFB1 (transforming growth factor-β, TGF-β) signaling pathway, and BAX plays a key role in apoptosis. However, a role of TGFBR2 or BAX mononucleotide mutation in colorectal cancer as a prognostic biomarker remains uncertain. METHODOLOGY/PRINCIPAL FINDINGS We utilized a database of 1072 rectal and colon cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusted for clinical, pathological and molecular features including the CpG island methylator phenotype (CIMP), LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. MSI-high was observed in 15% (162/1072) of all colorectal cancers. TGFBR2 and BAX mononucleotide mutations were detected in 74% (117/159) and 30% (48/158) of MSI-high tumors, respectively. In Kaplan-Meier analysis as well as univariate and multivariate Cox regression analyses, compared to microsatellite stable (MSS)/MSI-low cases, MSI-high cases were associated with superior colorectal cancer-specific survival [adjusted HR, 0.34; 95% confidence interval (CI), 0.20-0.57] regardless of TGFBR2 or BAX mutation status. Among MSI-high tumors, TGFBR2 mononucleotide mutation was associated with CIMP-high independent of other variables [multivariate odds ratio, 3.57; 95% CI, 1.66-7.66; p = 0.0011]. CONCLUSIONS TGFBR2 or BAX mononucleotide mutations are not associated with the patient survival outcome in MSI-high colorectal cancer. Our data do not support those mutations as prognostic biomarkers (beyond MSI) in colorectal carcinoma.
Collapse
|
|
21
|
Harrison S, Benziger H. The molecular biology of colorectal carcinoma and its implications: A review. Surgeon 2011; 9:200-10. [DOI: 10.1016/j.surge.2011.01.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2010] [Revised: 01/17/2011] [Accepted: 01/23/2011] [Indexed: 02/07/2023]
|
|
22
|
Abstract
CONTEXT Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy. OBJECTIVE To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed. DATA SOURCES Original research articles, review articles, and the authors' personal practice experience. CONCLUSIONS Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care.
Collapse
Affiliation(s)
- Anne Igbokwe
- Molecular Pathology Laboratory, BloodSource, Mather, CA 95655-4128, USA.
| | | |
Collapse
|
|
23
|
Stingo FC, Vannucci M. Variable selection for discriminant analysis with Markov random field priors for the analysis of microarray data. Bioinformatics 2010; 27:495-501. [PMID: 21159623 DOI: 10.1093/bioinformatics/btq690] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
MOTIVATION Discriminant analysis is an effective tool for the classification of experimental units into groups. Here, we consider the typical problem of classifying subjects according to phenotypes via gene expression data and propose a method that incorporates variable selection into the inferential procedure, for the identification of the important biomarkers. To achieve this goal, we build upon a conjugate normal discriminant model, both linear and quadratic, and include a stochastic search variable selection procedure via an MCMC algorithm. Furthermore, we incorporate into the model prior information on the relationships among the genes as described by a gene-gene network. We use a Markov random field (MRF) prior to map the network connections among genes. Our prior model assumes that neighboring genes in the network are more likely to have a joint effect on the relevant biological processes. RESULTS We use simulated data to assess performances of our method. In particular, we compare the MRF prior to a situation where independent Bernoulli priors are chosen for the individual predictors. We also illustrate the method on benchmark datasets for gene expression. Our simulation studies show that employing the MRF prior improves on selection accuracy. In real data applications, in addition to identifying markers and improving prediction accuracy, we show how the integration of existing biological knowledge into the prior model results in an increased ability to identify genes with strong discriminatory power and also aids the interpretation of the results.
Collapse
|
|
24
|
Yun JY, Uhm YK, Kim HJ, Lim SH, Chung JH, Shin MK, Yim SV, Lee MH. Transforming growth factor beta receptor II (TGFBR2) polymorphisms and the association with nonsegmental vitiligo in the Korean population. Int J Immunogenet 2010; 37:289-91. [PMID: 20518838 DOI: 10.1111/j.1744-313x.2010.00923.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The precise cause of vitiligo is unknown. However, autoimmunity is considered the most likely aetiology, especially in nonsegmental vitiligo (NSV). In this study we determined whether or not the transforming growth factor beta receptor II (TGFBR2) gene contributes to susceptibility for NSV in the Korean population. Blood samples were collected from 415 controls and 233 cases. We selected three single nucleotide polymorphisms (SNPs) in the TGFBR2 gene. The genotypes of the SNPs were determined using direct sequencing. All of the SNPs were significantly different between the vitiligo patients and controls (rs2005061, co-dominant, dominant, recessive, P < 0.05; rs3773645, co-dominant, dominant, recessive, P < 0.05; rs3773649, co-dominant, recessive, P < 0.05). In addition, haplotype 1 (CG) and haplotype 2 (GA) of the linkage disequilibrium (LD) block were also associated with a risk of NSV. The present study suggests that TGFBR2 might be related to NSV.
Collapse
Affiliation(s)
- J Y Yun
- Department of Clinical Pharmacology, School of Medicine, Kyung Hee University, Seoul, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Molecular pathology of RUNX3 in human carcinogenesis. Biochim Biophys Acta Rev Cancer 2009; 1796:315-31. [PMID: 19682550 DOI: 10.1016/j.bbcan.2009.07.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2009] [Accepted: 07/31/2009] [Indexed: 12/12/2022]
Abstract
A major goal of molecular biology is to elucidate the mechanisms underlying cancer development and progression in order to achieve early detection, better diagnosis and staging and novel preventive and therapeutic strategies. We feel that an understanding of Runt-related transcription factor 3 (RUNX3)-regulated biological pathways will directly impact our knowledge of these areas of human carcinogenesis. The RUNX3 transcription factor is a downstream effector of the transforming growth factor-beta (TGF-beta) signaling pathway, and has a critical role in the regulation of cell proliferation and cell death by apoptosis, and in angiogenesis, cell adhesion and invasion. We previously identified RUNX3 as a major gastric tumor suppressor by establishing a causal relationship between loss of function and gastric carcinogenesis. More recently, we showed that RUNX3 functions as a bona fide initiator of colonic carcinogenesis by linking the Wnt oncogenic and TGF-beta tumor suppressive pathways. Apart from gastric and colorectal cancers, a multitude of epithelial cancers exhibit inactivation of RUNX3, thereby making it a putative tumor suppressor in human neoplasia. This review highlights our current understanding of the molecular mechanisms of RUNX3 inactivation in the context of cancer development and progression.
Collapse
|
|
26
|
Vasilatos SN, Broadwater G, Barry WT, Baker JC, Lem S, Dietze EC, Bean GR, Bryson AD, Pilie PG, Goldenberg V, Skaar D, Paisie C, Torres-Hernandez A, Grant TL, Wilke LG, Ibarra-Drendall C, Ostrander JH, D'Amato NC, Zalles C, Jirtle R, Weaver VM, Seewaldt VL. CpG island tumor suppressor promoter methylation in non-BRCA-associated early mammary carcinogenesis. Cancer Epidemiol Biomarkers Prev 2009; 18:901-14. [PMID: 19258476 PMCID: PMC2667866 DOI: 10.1158/1055-9965.epi-08-0875] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Only 5% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known. METHODS CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic women at high risk for breast cancer. Promoter methylation targets included RARB (M3 and M4), ESR1, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1. RESULTS Although the overall frequency of CpG island promoter methylation events increased with age (P<0.0001), no specific methylation event was associated with age. In contrast, CpG island methylation of RARB M4 (P=0.051), INK4a/ARF (P=0.042), HIN-1 (P=0.044), and PRA (P=0.032), as well as the overall frequency of methylation events (P=0.004), was associated with abnormal Masood cytology. The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing. Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had CONCLUSIONS This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.
Collapse
Affiliation(s)
- Shauna N. Vasilatos
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Gloria Broadwater
- Cancer Center Biostatistics, Duke University Medical Center, Durham, North Carolina
| | - William T. Barry
- Cancer Center Biostatistics, Duke University Medical Center, Durham, North Carolina
| | - Joseph C. Baker
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Siya Lem
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Eric C. Dietze
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Gregory R. Bean
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Andrew D. Bryson
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Patrick G. Pilie
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Vanessa Goldenberg
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - David Skaar
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Carolyn Paisie
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | | | - Tracey L. Grant
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Lee G. Wilke
- Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | | | - Julie H. Ostrander
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Nicholas C. D'Amato
- Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Carola Zalles
- Department of Pathology, Yale-New Haven Medical Center, New Haven, Connecticut
| | - Randy Jirtle
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Valerie M. Weaver
- Department of Surgery, University of California, San Francisco, California
| | - Victoria L. Seewaldt
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
- Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| |
Collapse
|
|
27
|
Chowdhury S, Ammanamanchi S, Howell GM. Epigenetic Targeting of Transforming Growth Factor β Receptor II and Implications for Cancer Therapy. MOLECULAR AND CELLULAR PHARMACOLOGY 2009; 1:57-70. [PMID: 20414468 PMCID: PMC2857646 DOI: 10.4255/mcpharmacol.09.07] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.
Collapse
Affiliation(s)
- Sanjib Chowdhury
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 987696 Nebraska Medical Center, Omaha, Nebraska
| | - Sudhakar Ammanamanchi
- Division of Medical Oncology, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas
| | - Gillian M. Howell
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 987696 Nebraska Medical Center, Omaha, Nebraska
| |
Collapse
|
|
28
|
Nosho K, Kawasaki T, Chan AT, Ohnishi M, Suemoto Y, Kirkner GJ, Fuchs CS, Ogino S. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology 2008; 53:588-98. [PMID: 18983468 PMCID: PMC2719983 DOI: 10.1111/j.1365-2559.2008.03161.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIMS Cyclin D1 and cyclin-dependent kinases are commonly activated in colorectal cancer. Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. The aim was to clarify the relationship between cyclin D1, MSI and CIMP. METHODS AND RESULTS Among 865 colorectal cancers with MSI and CIMP data, 246 tumours (28.4%) showed cyclin D1 overexpression by immunohistochemistry. DNA methylation in p14 and eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) was quantified by real-time polymerase chain reaction (MethyLight). Both MSI-high and CIMP-high were associated with cyclin D1 overexpression (P < 0.0001). After tumours were stratified by MSI and CIMP status, the relationship between MSI-high and cyclin D1 persisted (P < or = 0.02), whereas the relationship between CIMP-high and cyclin D1 did not. Cyclin D1 overexpression was correlated with BRAF mutation (P = 0.0001), p27 loss (P = 0.0007) and p16 loss (P = 0.02), and inversely with p53 expression (P = 0.0002) and p21 loss (P < 0.0001). After stratification by MSI status, the inverse relationship between cyclin D1 and p21 loss still persisted (P < 0.008). CONCLUSIONS Cyclin D1 activation is associated with MSI and inversely with p21 loss in colorectal cancers. Cyclin D1 may play an important role in the development of MSI-high tumours, independent of CIMP status.
Collapse
Affiliation(s)
- Katsuhiko Nosho
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115 USA
| | - Takako Kawasaki
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115 USA
| | - Andrew T. Chan
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115 USA
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02115 USA
| | - Mutsuko Ohnishi
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115 USA
| | - Yuko Suemoto
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115 USA
| | - Gregory J. Kirkner
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115 USA
| | - Charles S. Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115 USA
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115 USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115 USA
- Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115 USA
- Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115 USA
| |
Collapse
|
|
29
|
Kim JC, Cho YK, Roh SA, Yu CS, Gong G, Jang SJ, Kim SY, Kim YS. Individual tumorigenesis pathways of sporadic colorectal adenocarcinomas are associated with the biological behavior of tumors. Cancer Sci 2008; 99:1348-54. [PMID: 18422752 PMCID: PMC11159463 DOI: 10.1111/j.1349-7006.2008.00819.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Clinicopathologic features of sporadic colorectal adenocarcinomas were compared using integrated data from 224 [corrected] patients subjected to curative resection. Individual steps in the tumorigenesis pathway, that is, adenomatosis polyposis coli (APC), Wnt-activated, base excision repair mutations, mismatch repair defects, RAF-mediated, transforming growth factor (TGF)-beta-suppressed, bone morphogenic protein (BMP)-suppressed, and p53 alterations, were examined in terms of genetic and epigenetic changes, as well as protein expression. Genetic and molecular alterations of right colon cancers were distinct from those of left colon and rectal cancers. Rectal cancers showed the attenuated phenotype of left colon cancers. Tumors most frequently displayed either TGF-beta- or BMP-suppressed alterations (81.2%), followed by RAF-mediated alterations (78.6%), and mismatch repair defects (38.4%), constituting a total of 24 integrated pathways. Tumors lacking APC mutations or carrying the RAF alteration (V600E) were frequently associated with lymphovascular invasion and lymph node metastasis (P < 0.05). Poorly differentiated or mucinous adenocarcinomas were generally associated with high level microsatellite instability, Axin2 suppression, TGF-beta1 or BMPR1A suppression, loss of heterozygosity of D18S46 or D18S474, and absence of base excision repair mutations (P < 0.0001-0.05). Early tumor recurrence was significantly correlated with lack of APC mutations (P = 0.036). Moreover, tumors that concurrently displayed APC/Wnt-activated, TGF-beta/BMP-suppressed, and p53 alterations were significantly predisposed to early recurrence (P = 0.026). Our data clearly indicate that particular steps or pathways of colorectal tumorigenesis are closely associated with characteristic clinicopathologic features that, in turn, determine biological behavior, such as tumor growth, invasion, and recurrence.
Collapse
Affiliation(s)
- Jin C Kim
- Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, 388-1 Poongnap-2-Dong Songpa-Ku, Seoul 138-736, Republic of Korea.
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Chittenden TW, Howe EA, Culhane AC, Sultana R, Taylor JM, Holmes C, Quackenbush J. Functional classification analysis of somatically mutated genes in human breast and colorectal cancers. Genomics 2008; 91:508-11. [PMID: 18434084 PMCID: PMC2492759 DOI: 10.1016/j.ygeno.2008.03.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 03/04/2008] [Accepted: 03/05/2008] [Indexed: 11/22/2022]
Abstract
A recent study published by Sjoblom and colleagues [T. Sjoblom, S. Jones, L.D. Wood, D.W. Parsons, J. Lin, T.D. Barber, D. Mandelker, R.J. Leary, J. Ptak, N. Silliman, S. Szabo, P. Buckhaults, C. Farrell, P. Meeh, S.D. Markowitz, J. Willis, D. Dawson, J.K. Willson, A.F. Gazdar, J. Hartigan, L. Wu, C. Liu, G. Parmigiani, B.H. Park, K.E. Bachman, N. Papadopoulos, B. Vogelstein, K.W. Kinzler, V.E. Velculescu, The consensus coding sequences of human breast and colorectal cancers. Science 314 (2006) 268-274.] performed comprehensive sequencing of 13,023 human genes and identified mutations in genes specific to breast and colorectal tumors, providing insight into organ-specific tumor biology. Here we present a systematic analysis of the functional classifications of Sjoblom's "CAN" genes, a subset of these validated mutant genes, that identifies novel organ-specific biological themes and molecular pathways associated with disease-specific etiology. This analysis links four somatically mutated genes associated with diverse oncological types to colorectal and breast cancers through established TGF-beta1-regulated interactions, revealing mechanistic differences in these cancers and providing potential diagnostic and therapeutic targets.
Collapse
Affiliation(s)
- Thomas W. Chittenden
- Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
- Department of Statistics, University of Oxford, Oxford, UK
| | - Eleanor A. Howe
- Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Aedin C. Culhane
- Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
| | - Razvan Sultana
- Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jennifer M. Taylor
- Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Chris Holmes
- Department of Statistics, University of Oxford, Oxford, UK
- MRC Mammalian Genetics Unit, Harwell, UK
| | - John Quackenbush
- Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
| |
Collapse
|
|
31
|
Nosho K, Yamamoto H, Takahashi T, Mikami M, Hizaki K, Maehata T, Taniguchi H, Yamaoka S, Adachi Y, Itoh F, Imai K, Shinomura Y. Correlation of laterally spreading type and JC virus with methylator phenotype status in colorectal adenoma. Hum Pathol 2008; 39:767-775. [PMID: 18284934 DOI: 10.1016/j.humpath.2007.10.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 09/24/2007] [Accepted: 10/04/2007] [Indexed: 12/13/2022]
Abstract
Accurate frequencies of CpG island methylator phenotype (CIMP) have not been determined for laterally spreading tumors (LSTs) and other flat-type colorectal adenomas, and the role of JC virus T-antigen (T-Ag) in these tumors is unclear. We used MethyLight assay to analyze the relationship between CIMP status and clinicopathologic characteristics in tissue from 72 LST of granular-type (LST-G), 35 LST of nongranular-type (LST-NG), 54 protruded-type adenomas, and 89 colorectal cancers. We also investigated the relationship between CIMP status and T-Ag by immunohistochemistry. With the use of 5 markers for CIMP status, tumors were classified as CIMP-high (> or = 4/5 methylated promoters), CIMP-low (1/5 to 3/5 methylated promoters), or CIMP-0 (no methylated promoters). The proportion classified as CIMP-0 status was 5.6% for protruded-type adenoma, 17.1% for LST-NG, and 29.2% for LST-G (LST-G versus protruded-type adenoma, P = .001). CIMP-low status was established for 62.5% of LST-G, 74.3% of LST-NG, and 81.5% of protruded-type adenomas. CIMP-high status was established for 8.3% of LST-G, 8.6% of LST-NG, and 12.9% of protruded-type adenomas. The proportions of CIMP-low and CIMP-high status were not significantly different between the 3 groups. Multiple logistic analysis showed that LST-G appearance was the only significant factor for identifying CIMP-0 status. BRAF mutation was the only significant factor for identifying CIMP-high status. T-Ag expression increased with CIMP status and was not associated with macroscopic appearance. In conclusion, among colorectal adenomas, CIMP-high status was determined by BRAF mutation and not by macroscopic type, unlike CIMP-0. JC virus T-Ag may be important in determining methylator phenotype.
Collapse
Affiliation(s)
- Katsuhiko Nosho
- First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
IGFBP3 promoter methylation in colorectal cancer: relationship with microsatellite instability, CpG island methylator phenotype, and p53. Neoplasia 2008; 9:1091-8. [PMID: 18084616 DOI: 10.1593/neo.07760] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2007] [Revised: 10/02/2007] [Accepted: 10/05/2007] [Indexed: 12/14/2022] Open
Abstract
Insulin-like growth factor binding protein 3 (IGFBP3), which is induced by wild-type p53, regulates IGF and interacts with the TGF-beta pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP), which is associated with microsatellite instability (MSI) and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight), we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1). IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41) than in MSI-high CIMP-high (49% = 44/90, P < .0001), MSI-high non-CIMP-high (17% = 6/36, P < .0001), and non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001). Among CIMP-high tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001), but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02). In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, and this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/CIMP), single molecular events (e.g., IGFBP3 methylation, TP53 mutation, and TGFBR2 mutation), and the related pathways.
Collapse
|
|
33
|
Abstract
Molecular classification of colorectal cancer is evolving. As our understanding of colorectal carcinogenesis improves, we are incorporating new knowledge into the classification system. In particular, global genomic status [microsatellite instability (MSI) status and chromosomal instability (CIN) status] and epigenomic status [CpG island methylator phenotype (CIMP) status] play a significant role in determining clinical, pathological and biological characteristics of colorectal cancer. In this review, we discuss molecular classification and molecular correlates based on MSI status and CIMP status in colorectal cancer. Studying molecular correlates is important in cancer research because it can 1) provide clues to pathogenesis, 2) propose or support the existence of a new molecular subtype, 3) alert investigators to be aware of potential confounding factors in association studies, and 4) suggest surrogate markers in clinical or research settings.
Collapse
Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
| | | |
Collapse
|
|
34
|
Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Kirkner GJ, Dehari R, Meyerhardt JA, Fuchs CS, Ogino S. Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer. Neoplasia 2007; 9:569-77. [PMID: 17710160 PMCID: PMC1939932 DOI: 10.1593/neo.07334] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Revised: 05/21/2007] [Accepted: 05/21/2007] [Indexed: 11/18/2022] Open
Abstract
The WNT/beta-catenin (CTNNB1) pathway is commonly activated in the carcinogenic process. Cross-talks between the WNT and cyclooxygenase-2 (COX-2 or PTGS2)/prostaglandin pathways have been suggested. The relationship between beta-catenin activation and microsatellite instability (MSI) in colorectal cancer has been controversial. The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, which is associated with MSI-high. However, no study has examined the relationship between beta-catenin activation and CIMP status. Using 832 population-based colorectal cancer specimens, we assessed beta-catenin localization by immunohistochemistry. We quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A(p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). MSI-high, CIMP-high, and BRAF mutation were associated inversely with cytoplasmic and nuclear beta-catenin expressions (i.e., beta-catenin activation) and associated positively with membrane expression. The inverse relation between beta-catenin activation and CIMP was independent of MSI. COX-2 overexpression correlated with cytoplasmic beta-catenin expression (even after tumors were stratified by CIMP status), but did not correlate significantly with nuclear or membrane expression. In conclusion, beta-catenin activation is inversely associated with CIMP-high independent of MSI status. Cytoplasmic beta-catenin is associated with COX-2 overexpression, supporting the role of cytoplasmic beta-catenin in stabilizing PTGS2 (COX-2) mRNA.
Collapse
Affiliation(s)
- Takako Kawasaki
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Katsuhiko Nosho
- Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
| | - Mutsuko Ohnishi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Yuko Suemoto
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Gregory J Kirkner
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Reiko Dehari
- Department of Pathology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
| |
Collapse
|
|
35
|
Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M, Fuchs CS. Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn 2007; 9:305-14. [PMID: 17591929 PMCID: PMC1899428 DOI: 10.2353/jmoldx.2007.060170] [Citation(s) in RCA: 278] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by an independent, large dataset. Using MethyLight assays on 920 colorectal cancers from two large prospective cohort studies, we quantified DNA methylation in eight CIMP-specific markers [the above five plus CDKN2A (p16), CRABP1, and MLH1]. A CIMP-high cutoff was set at > or = 6/8 or > or = 5/8 methylated promoters, based on tumor distribution and BRAF/KRAS mutation frequencies. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated > or = 85% sensitivity and > or = 80% specificity, indicating overall good concordance in methylation patterns and good performance of these markers. Based on sensitivity, specificity, and false positives and negatives, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1, and CDKN2A. In conclusion, a panel of markers including at least RUNX3, CACNA1G, IGF2, and MLH1 can serve as a sensitive and specific marker panel for CIMP-high.
Collapse
Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | | | | | | | | | | |
Collapse
|