Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk

Abstract

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10−8 to 9.22 × 10−21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.

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Figure 1: Forest plots for risk-associated variants in the six newly identified loci.
Figure 2: Association of selected risk variants identified in this study with gene expression in colon tumor tissue.

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Acknowledgements

The authors are solely responsible for the scientific content of this paper. The sponsors of this study had no role in study design, data collection, analysis or interpretation, writing of the report or the decision for submission. We thank all study participants and research staff of all parent studies for their contributions and commitment to this project, R. Courtney for DNA preparation, J. He for data processing and analyses, X. Guo for suggestions on bioinformatics analysis, and M.J. Daly and B.J. Rammer for editing and preparing the manuscript. The work at the Vanderbilt University School of Medicine was supported by US National Institutes of Health (NIH) grants R37CA070867, R01CA082729, R01CA124558, R01CA148667 and R01CA122364, as well as by Ingram Professorship and Research Reward funds from the Vanderbilt University School of Medicine. Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH, R37CA070867), the Shanghai Men's Health Study (US NIH, R01CA082729), the Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Shanghai Colorectal Cancer Study 3 (US NIH, R37CA070867 and Ingram Professorship funds), the Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04; the National Basic Research Program, 2011CB504303, contributing only controls; the Natural Science Foundation of China, 81072383, contributing only controls), the Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from the Korea Center for Disease Control and Prevention and the Jeonnam Regional Cancer Center), the Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, 17015018 and 221S0001), the Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276; National Cancer Center Korea, 0910220), the Korea-Seoul Colorectal Cancer Study (none reported) and the KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control, 1220180; Seoul R&D Program, 10526).

We also thank all participants, staff and investigators from the GECCO, CORECT and CCFR consortia for making it possible to present results from populations of European ancestry for the new CRC-associated loci identified among East Asians. GECCO, CORECT and CCFR are directed by U. Peters, S. Gruber and G. Casey, respectively. Complete lists of investigators from the GECCO, CORECT and CCFR consortia are provided below.

Investigators (institution and location) in the GECCO consortium include (in alphabetical order) John A. Baron (Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA), Sonja I. Berndt (Division of Cancer Epidemiology and Genetics, National Cancer Institute, US NIH, Bethesda, Maryland, USA), Stéphane Bezieau (Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France), Hermann Brenner (Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany), Bette J. Caan (Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA), Christopher S. Carlson (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, School of Public Health, University of Washington, Seattle, Washington, USA), Graham Casey (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Andrew T. Chan (Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA and Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA), Jenny Chang-Claude (Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany), Stephen J. Chanock (Division of Cancer Epidemiology and Genetics, National Cancer Institute, US NIH, Bethesda, Maryland, USA), David V. Conti (Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA), Keith Curtis (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), David Duggan (Translational Genomics Research Institute, Phoenix, Arizona, USA), Charles S. Fuchs (Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA and Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA), Steven Gallinger (Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada and Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada), Edward L. Giovannucci (Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA), Stephen B. Gruber (University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Robert W. Haile (Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA), Tabitha A. Harrison (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Richard B. Hayes (Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA), Michael Hoffmeister (Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany), John L. Hopper (Melbourne School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia), Li Hsu (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA and Department of Biostatistics, University of Washington, Seattle, Washington, USA), Thomas J. Hudson (Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada), David J. Hunter (Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA), Carolyn M. Hutter (Division of Cancer Control and Population Sciences, National Cancer Institute, US NIH, Bethesda, Maryland, USA), Rebecca D. Jackson (Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio, USA), Mark A. Jenkins (Melbourne School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia), Shuo Jiao (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Sébastien Küry (Service de Génétique Médicale, CHU Nantes, Nantes, France), Loic Le Marchand (Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA), Mathieu Lemire (Ontario Institute for Cancer Research, Toronto, Ontario, Canada), Noralane M. Lindor (Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona, USA), Jing Ma (Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA), Polly A. Newcomb (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA and Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA), Ulrike Peters (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA and Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA), John D. Potter (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA, Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA and Centre for Public Health Research, Massey University, Palmerston North, New Zealand), Conghui Qu (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Thomas Rohan (Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA), Robert E. Schoen (Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA), Fredrick R. Schumacher (Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA), Daniela Seminara (Division of Cancer Control and Population Sciences, National Cancer Institute, US NIH, Bethesda, Maryland, USA), Martha L. Slattery (Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA), Stephen N. Thibodeau (Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA and Department of Laboratory Genetics, Mayo Clinic, Rochester, Minnesota, USA), Emily White (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA and Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA) and Brent W. Zanke (Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada).

Investigators (institution and location) from the CORECT consortium include (in alphabetical order) Kendra Blalock (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Peter T. Campbell (Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA), Graham Casey (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), David V. Conti (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Christopher K. Edlund (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Jane Figueiredo (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), W. James Gauderman (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Jian Gong (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Roger C. Green (Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada), Stephen B. Gruber (University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), John F. Harju (University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA), Tabitha A. Harrison (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Eric J. Jacobs (Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA), Mark A. Jenkins (Melbourne School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia), Shuo Jiao (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Li Li (Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA), Yi Lin (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Frank J. Manion (University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA), Victor Moreno (Institut d'Investigació Biomèdica de Bellvitge, Institut Catala d'Oncologia, Hospitalet, Barcelona, Spain), Bhramar Mukherjee (University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA), Ulrike Peters (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Leon Raskin (University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Fredrick R. Schumacher (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA), Daniela Seminara (Division of Cancer Control and Population Sciences, National Cancer Institute, US NIH, Bethesda, Maryland, USA), Gianluca Severi (Melbourne School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia), Stephanie L. Stenzel (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA) and Duncan C. Thomas (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA).

The CCFR consortium is represented by Graham Casey (Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA).

We also thank B. Buecher of ASTERISK; U. Handte-Daub, M. Celik, R. Hettler-Jensen, U. Benscheid and U. Eilber of DACHS; and P. Soule, H. Ranu, I. Devivo, D.J. Hunter, Q. Guo, L. Zhu and H. Zhang of HPFS, NHS and PHS, as well as the following state cancer registries for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington and Wyoming. We thank C. Berg and P. Prorok of PLCO; T. Riley of Information Management Services, Inc.; B. O'Brien of Westat, Inc.; B. Kopp and W. Shao of SAIC-Frederick; the WHI investigators (see https://www.whi.org/researchers/SitePages/Write%20a%20Paper.aspx) and the GECCO Coordinating Center. Participating studies (grant support) in the GECCO, CORECT and CCFR GWAS meta-analysis are GECCO (US NIH, U01CA137088 and R01CA059045), DALS (US NIH, R01CA048998), DACHS (German Federal Ministry of Education and Research, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404 and 01ER0814), HPFS (US NIH, P01CA055075, UM1CA167552, R01137178 and P50CA127003), NHS (US NIH, R01137178, P50CA127003 and P01CA087969), OFCCR (US NIH, U01CA074783), PMH (US NIH, R01CA076366), PHS (US NIH, R01CA042182), VITAL (US NIH, K05CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C and 268200764316C) and PLCO (US NIH, Z01CP 010200, U01HG004446 and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH, U19CA148107) with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, US NIH under RFA CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01CA097735), the Familial Colorectal Neoplasia Collaborative Group (US NIH, U01CA074799) (University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01CA074800), the Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01CA074783), the Seattle Colorectal Cancer Family Registry (US NIH, U01CA074794) and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The GWAS work was supported by a National Cancer Institute grant (US NIH, U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J. Hudson and B.W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through support from the Ontario Ministry of Economic Development and Innovation. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (CGEMS prostate cancer scan, phs000207.v1.p1; CGEMS pancreatic cancer scan, phs000206.v4.p3; and GWAS of Lung Cancer and Smoking, phs000093.v2.p2, which was funded by Z01CP 010200, U01HG004446 and U01HG 004438 from the US NIH).

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W.Z. conceived and directed the Asia Colorectal Cancer Consortium and the Shanghai-Vanderbilt Colorectal Cancer Genetics Project. W.-H.J. and Y.-X.Z.; K. Matsuda; S.-S.K.; K. Matsuo; X.-O.S., Y.-B.X. and Y.-T.G.; A.S.; S.H.J.; and D.-H.K. directed CRC projects for the Guangzhou Colorectal Cancer Study, the BioBank Japan Colorectal Cancer Study, the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC), the Aichi Colorectal Cancer Study, the Shanghai studies, the Korea-NCC (National Cancer Center) Colorectal Cancer Study, the KCPS-II Colorectal Cancer Study and the Korea-Seoul Colorectal Cancer Study, respectively. B.Z., Q.C. and W.W. coordinated the project. Q.C. directed laboratory operations. J.S. performed the genotyping experiments. B.Z. performed the statistical and bioinformatics analyses. W.W. contributed to the statistical analyses and data interpretation. A.T. conducted the statistical analyses and imputation for BioBank Japan. B.Z., W.W. and J.L. managed the data. Y.Z. and B.Z. performed the expression analysis for TCGA data. B.Z. and W.Z. wrote the manuscript with significant contributions from X.-O.S., Q.C., J.L., W.W., B.L. and Y.Z. All authors contributed to data and biological sample collection in the original studies included in this project and to manuscript revision. All authors have reviewed and approved the content of the paper.

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Correspondence to Wei Zheng.

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A complete list of members and affiliations appears in the Acknowledgments.

A complete list of members and affiliations appears in the Acknowledgments.

A complete list of members and affiliations appears in the Acknowledgments.

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Zhang, B., Jia, WH., Matsuda, K. et al. Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk. Nat Genet 46, 533–542 (2014). https://doi.org/10.1038/ng.2985

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