Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Broad Institute of MIT and Harvard Cambridge MA

Department of Biology University of Pisa Pisa Italy

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA

Department of Epidemiology Richard M Fairbanks School of Public Health Indiana University Indianapolis IN

Department of Health Sciences Research Mayo Clinic Arizona Scottsdale AZ

Department of Internal Medicine University of Utah Health Sciences Center Salt Lake City UT

Department of Medical Sciences University of Turin Turin Italy

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA

Department of Molecular Biology of Cancer Institute of Experimental Medicine The Czech Academy of Sciences Prague Czech Republic

Department of Oncologic Pathology Dana Farber Cancer Institute Boston MA

Department of Surgery Mount Sinai Hospital Toronto ON Canada

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Rockville MD

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology Department of Population Health New York University School of Medicine New York NY

Division of Gastroenterology Massachusetts General Hospital Boston MA

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Epidemiology Program Research Cancer Center of Hawaii University of Hawaii Honolulu HI

Epidemiology Research Program American Cancer Society Atlanta GA

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

German Cancer Consortium Heidelberg Germany

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Italian Institute for Genomic Medicine Turin Italy

Kaiser Permanente Medical Care Program of Northern California Oakland CA

Melbourne School of Population Health The University of Melbourne Melbourne VIC Australia

Prevention and Cancer Control Cancer Care Ontario Toronto ON Canada

Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston MA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA

Public Health Sciences University of Virginia Charlottesville VA

School of Public Health University of Washington Seattle WA

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes France

Stanford University School of Medicine Stanford CA

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