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Grant Details

Grant Number: 5R03CA153323-02 Interpret this number
Primary Investigator: Newcomb, Polly
Organization: Fred Hutchinson Cancer Research Center
Project Title: Gwas Identified Colorectal Cancer Snps and Colorectal Polyp Risk
Fiscal Year: 2011


Abstract

DESCRIPTION (provided by applicant): Adenomatous polyps, also referred to as adenomas, are well-established precursor lesions to colorectal cancer (CRC). Other polyps commonly found in the colon and rectum is hyperplastic polyps (HPs). HPs have long been considered benign lesions. However, recent evidence suggests that HPs and the histogenetically- related serrated adenomas may progress to malignancy along a separate "serrated pathway". There is compelling and consistent data that links both high and low penetrance genes to CRC, and it is likely that specific genes or genotypes may be associated with different colorectal neoplastic pathways. Recently, genomic studies of colorectal cancer have made great strides with genome-wide association studies (GWAS) identifying 10 CRC susceptibility loci at different sites in the human genome; these loci may be relevant to the genesis and progression of precursor lesions, such as certain types of colorectal polyps. In this application, we propose to determine the risk of adenomas and HPs associated with: 1) the specific polymorphisms identified through GWAS, including the following: 8q24 (rs6983267), 18q21/SMAD7 (rs4939827), 15q13/CRAC1 (rs4779584), 10p14 (rs10795668), 8q23.3/EIF3H (rs16892766), 11q23 (rs3802842), 14q22.2/BMP4 (rs4444235), 16q22.1/CDH1 (rs9929218), 19q13.1/RHPN2 (rs10411210), 20p12.3 (rs961253), and 2) the genes or regions of the genome that house these loci using a tagSNP approach. This research is ancillary to an existing study, "Colon cancer pathways: hyperplastic polyps and adenomas" (CA 097325), aimed at comparing the epidemiologic risk factors and molecular features of adenomas and HPs with the goal of learning more about the clinical importance of HPs and the serrated adenoma pathway. Our study population includes 1,765 colonoscopy-defined adenoma cases, HP cases, and controls who were members of a large integrated health plan. All participants completed standardized interviews covering demographics and colorectal-cancer risk factors. In addition, study participants provided buccal cell samples for DNA analysis, and all cases are undergoing a standardized pathology review to confirm the diagnosis and to further categorize the pathologic features of their polyps. This proposed project will increase the body of knowledge surrounding the mechanisms for early colorectal carcinogenesis and help elucidate the genes important to different colorectal cancer pathways. In addition, it may provide clues about the clinical importance of HPs and other polyps hypothesized to be on the serrated pathway, including sessile serrated polyps, by linking these lesions to known CRC susceptibility genes. PUBLIC HEALTH RELEVANCE: Project Narrative Most colorectal cancers (CRC) arise from polyps, but the genes important to colorectal polyps have not been fully characterized, and the debate about the clinical importance of some polyps, such as hyperplastic polyps (HPs) is ongoing. Recent genome wide association studies of CRC have indentified 10 loci that are associated with CRC. By examining these same loci in relation to adenomas and HPs we will learn more about genes and mechanisms involved in early carcinogenesis and further characterize the malignant potential of HPs.



Publications

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.
Authors: Dimou N. , Mori N. , Harlid S. , Harbs J. , Martin R.M. , Smith-Byrne K. , Papadimitriou N. , Bishop D.T. , Casey G. , Colorado-Yohar S.M. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 07; 30(7), p. 1336-1348.
EPub date: 2021-04-20.
PMID: 33879453
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Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.
Authors: Dimou N. , Yarmolinsky J. , Bouras E. , Tsilidis K.K. , Martin R.M. , Lewis S.J. , Gram I.T. , Bakker M.F. , Brenner H. , Figueiredo J.C. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 05; 30(5), p. 953-964.
EPub date: 2021-03-02.
PMID: 33653810
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Circulating adipokine concentrations and risk of five obesity-related cancers: A Mendelian randomization study.
Authors: Dimou N.L. , Papadimitriou N. , Mariosa D. , Johansson M. , Brennan P. , Peters U. , Chanock S.J. , Purdue M. , Bishop D.T. , Gago-Dominquez M. , et al. .
Source: International journal of cancer, 2021-04-01; 148(7), p. 1625-1636.
EPub date: 2020-10-26.
PMID: 33038280
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A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.
Authors: Nounu A. , Greenhough A. , Heesom K.J. , Richmond R.C. , Zheng J. , Weinstein S.J. , Albanes D. , Baron J.A. , Hopper J.L. , Figueiredo J.C. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 03; 30(3), p. 564-575.
EPub date: 2020-12-14.
PMID: 33318029
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Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.
Authors: Guo X. , Lin W. , Wen W. , Huyghe J. , Bien S. , Cai Q. , Harrison T. , Chen Z. , Qu C. , Bao J. , et al. .
Source: Gastroenterology, 2021 03; 160(4), p. 1164-1178.e6.
EPub date: 2020-10-12.
PMID: 33058866
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Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.
Authors: Bull C.J. , Bell J.A. , Murphy N. , Sanderson E. , Davey Smith G. , Timpson N.J. , Banbury B.L. , Albanes D. , Berndt S.I. , B├ęzieau S. , et al. .
Source: BMC medicine, 2020-12-17; 18(1), p. 396.
EPub date: 2020-12-17.
PMID: 33327948
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Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.
Authors: Murphy N. , Carreras-Torres R. , Song M. , Chan A.T. , Martin R.M. , Papadimitriou N. , Dimou N. , Tsilidis K.K. , Banbury B. , Bradbury K.E. , et al. .
Source: Gastroenterology, 2020 04; 158(5), p. 1300-1312.e20.
EPub date: 2019-12-27.
PMID: 31884074
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Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.
Authors: Lu Y. , Kweon S.S. , Cai Q. , Tanikawa C. , Shu X.O. , Jia W.H. , Xiang Y.B. , Huyghe J.R. , Harrison T.A. , Kim J. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 02; 29(2), p. 477-486.
EPub date: 2019-12-11.
PMID: 31826910
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Variation in the association between colorectal cancer susceptibility loci and colorectal polyps by polyp type.
Authors: Burnett-Hartman A.N. , Newcomb P.A. , Hutter C.M. , Peters U. , Passarelli M.N. , Schwartz M.R. , Upton M.P. , Zhu L.C. , Potter J.D. , Makar K.W. .
Source: American journal of epidemiology, 2014-07-15; 180(2), p. 223-32.
EPub date: 2014-05-29.
PMID: 24875374
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