Original Investigation

Human Genetics

, Volume 131, Issue 2, pp 217-234

First online:

Meta-analysis of new genome-wide association studies of colorectal cancer risk

  • Ulrike PetersAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research CenterDepartment of Epidemiology, School of Public Health, University of Washington Email author 
  • , Carolyn M. HutterAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research Center
  • , Li HsuAffiliated withBiostatistics and Biomathematics Program, Fred Hutchinson Cancer Research Center
  • , Fredrick R. SchumacherAffiliated withDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California
  • , David V. ContiAffiliated withDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California
  • , Christopher S. CarlsonAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research Center
  • , Christopher K. EdlundAffiliated withKeck School of Medicine, University of Southern California
  • , Robert W. HaileAffiliated withDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California
  • , Steven GallingerAffiliated withDepartment of Surgery, Toronto General Hospital, University Health Network
    • , Brent W. ZankeAffiliated withClinical Epidemiology Program, Ottawa Hospital Research Institute
    • , Mathieu LemireAffiliated withOntario Institute for Cancer Research
    • , Jagadish RangrejAffiliated withOntario Institute for Cancer Research
    • , Raakhee VijayaraghavanAffiliated withTranslational Genomics Research Institute
    • , Andrew T. ChanAffiliated withDivision of Gastroenterology, Massachusetts General Hospital, Harvard Medical SchoolChanning Laboratory, Brigham and Women’s Hospital and Harvard Medical School
    • , Aditi HazraAffiliated withChanning Laboratory, Brigham and Women’s Hospital and Harvard Medical SchoolProgram in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health
    • , David J. HunterAffiliated withProgram in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health
    • , Jing MaAffiliated withChanning Laboratory, Brigham and Women’s Hospital and Harvard Medical School
    • , Charles S. FuchsAffiliated withChanning Laboratory, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute
    • , Edward L. GiovannucciAffiliated withChanning Laboratory, Brigham and Women’s Hospital and Harvard Medical SchoolDepartments of Epidemiology and Nutrition, Harvard School of Public Health
    • , Peter KraftAffiliated withProgram in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health
    • , Yan LiuAffiliated withDallas Research Center, Stephens & Associates
    • , Lin ChenAffiliated withDepartment of Health Studies, University of Chicago
    • , Shuo JiaoAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research Center
    • , Karen W. MakarAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research Center
    • , Darin TavernaAffiliated withTranslational Genomics Research Institute
    • , Stephen B. GruberAffiliated withDepartment of Internal Medicine, University of Michigan
    • , Gad RennertAffiliated withDepartment of Community Medicine and Epidemiology, Carmel Medical Center and Technion Faculty of Medicine
    • , Victor MorenoAffiliated withBiostatistics and Bioinformatics Unit, Catalan Institute of Oncology-IDIBELL
    • , Cornelia M. UlrichAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research CenterDepartment of Epidemiology, School of Public Health, University of WashingtonDivision of Preventive Oncology, German Cancer Research Center
    • , Michael O. WoodsAffiliated withDiscipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland
    • , Roger C. GreenAffiliated withDiscipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland
    • , Patrick S. ParfreyAffiliated withDiscipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland
    • , Ross L. PrenticeAffiliated withDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center
    • , Charles KooperbergAffiliated withDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center
    • , Rebecca D. JacksonAffiliated withDivision of Endocrinology, Diabetes and Metabolism, Ohio State University
    • , Andrea Z. LaCroixAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research Center
    • , Bette J. CaanAffiliated withDivision of Research, Kaiser Permanente Medical Care Program
    • , Richard B. HayesAffiliated withDivision of Epidemiology, Department of Environmental Medicine, New York University School of Medicine
    • , Sonja I. BerndtAffiliated withDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
    • , Stephen J. ChanockAffiliated withDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
    • , Robert E. SchoenAffiliated withDepartment of Epidemiology, University of Pittsburgh Medical Center
    • , Jenny Chang-ClaudeAffiliated withDivision of Cancer Epidemiology, German Cancer Research Center
    • , Michael HoffmeisterAffiliated withDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center
    • , Hermann BrennerAffiliated withDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center
    • , Bernd FrankAffiliated withDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center
    • , Stéphane BézieauAffiliated withService de Génétique Médicale, Pôle de Biologie, Centre Hospitalier Universitaire (CHU) de Nantes
    • , Sébastien KüryAffiliated withService de Génétique Médicale, Pôle de Biologie, Centre Hospitalier Universitaire (CHU) de Nantes
    • , Martha L. SlatteryAffiliated withDepartment of Internal Medicine, University of Utah Health Sciences Center
    • , John L. HopperAffiliated withCentre for Molecular, Environmental, Genetic, and Analytical Epidemiology, University of Melbourne
    • , Mark A. JenkinsAffiliated withCentre for Molecular, Environmental, Genetic, and Analytical Epidemiology, University of Melbourne
    • , Loic Le MarchandAffiliated withEpidemiology Program, Cancer Research Center of Hawai’i, University of Hawai’i at Manoa
    • , Noralane M. LindorAffiliated withDepartment of Medical Genetics, Mayo Clinic
    • , Polly A. NewcombAffiliated withCancer Prevention Program, Fred Hutchinson Cancer Research Center
    • , Daniela SeminaraAffiliated withDivision of Cancer Control and Population Sciences, National Cancer Institute
    • , Thomas J. HudsonAffiliated withOntario Institute for Cancer ResearchDepartments of Medical Biophysics and Molecular Genetics, University of Toronto
    • , David J. DugganAffiliated withTranslational Genomics Research Institute
    • , John D. PotterAffiliated withDepartment of Epidemiology, School of Public Health, University of WashingtonDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center
    • , Graham CaseyAffiliated withDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California Email author 

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Abstract

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10−5). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10−4). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.