Abstract

To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10−7 to 3.77 × 10−10 in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10−10 for rs647161 (5q31.1), 6.64 × 10−9 for rs2423279 (20p12.3) and 3.06 × 10−8 for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.

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Acknowledgements

The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The authors wish to thank the study participants and research staff for their contributions and commitment to this project, R. Courtney for DNA preparation, J. He for data processing and analyses, and M.J. Daly for clerical support in manuscript preparation. This research was supported in part 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. Participating studies (grant support) in the consortium are as follows: Shanghai Women's Health Study (US NIH, R37CA070867), Shanghai Men's Health Study (US NIH, R01CA082729), Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04, and the National Basic Research Program, 2011CB504303, contributing only controls; the Natural Science Foundation of China, 81072383, contributing only controls), Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, the 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), Korea–National Cancer Center Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276; National Cancer Center Korea, 0910220), Korea-Seoul Colorectal Cancer Study (none reported) and KCPS-II colorectal Cancer Study (National R&D Program for Cancer Control, 0920330; Seoul R&D Program, 10526).

We wish to thank all participants, staff and investigators of GECCO and CCFR for making it possible to present the results in individuals of European ancestry for new CRC susceptibility loci identified in east Asians. Investigators (institution and location) from GECCO and CCFR who provided support for this project include (in alphabetical order) Aaron K. Aragaki (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), 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, Katja Butterbach (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, Seattle, Washington, USA, and School of Public Health, University of Washington, Seattle, Washington, USA), Graham Casey (Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA), Andrew T. Chan (Division of Gastroenterology, Harvard Medical School and Massachusetts General Hospital, 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), Lin S. Chen (Department of Health Studies, University of Chicago, Chicago, Illinois, USA), Gerhard A. Coetzee (Keck School of Medicine, University of Southern California, Los Angeles, California, USA), Simon G. Coetzee (Keck School of Medicine, University of Southern California, Los Angeles, California, 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), Todd L. Edwards (Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, 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, and Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA), Stephanie M. Gogarten (School of Public Health, University of Washington, Seattle, Washington, USA), Stephen B. Gruber (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), Charles Kooperberg (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Sébastien Küry (Service de Génétique Médicale, CHU Nantes, Nantes, France), Andrea Z. LaCroix (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), Cathy C. Laurie (Department of Biostatistics, University of Washington, Seattle, Washington, USA), Cecelia A. Laurie (Department of Biostatistics, University of Washington, Seattle, Washington, USA), Loic Le Marchand (Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA), Mathieu Lemire (Ontario Institute for Cancer Research, Toronto, Ontario, Canada), David Levine (School of Public Health, University of Washington, Seattle, Washington, USA), Noralane M. Lindor (Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona, USA), Yan Liu (Stephens and Associates, Carrollton, Texas, USA), Jing Ma (Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA), Karen W. Makar (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 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), Ross L. Prentice (Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA), 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), Darin Taverna (Translational Genomics Research Institute, Phoenix, Arizona, USA), Stephen N. Thibodeau (Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA, and Department of Pathology and Laboratory Genetics, Mayo Clinic, Rochester, Minnesota, USA), Cornelia M. Ulrich (Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany, 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), Raakhee Vijayaraghavan (Genetic Basis of Human Disease Division, Translational Genomics Research Institute, Phoenix, Arizona, USA), Bruce Weir (Department of Biostatistics, University of Washington, Seattle, Washington, 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).

We also thank B. Buecher of ASTERISK; U. Handte-Daub, M. Celik, R. Hettler-Jensen, U. Benscheid and U. Eilber of DACHS; P. Soule, H. Ranu, I. Devivo, D. Hunter, Q. Guo, L. Zhu and H. Zhang of HPFS, NHS and PHS; 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; investigators from the Women's Health Initiative (WHI; see URLs) and the GECCO Coordinating Center. Participating studies (grant support) in the GECCO and CCFR GWAS meta-analysis are as follows: GECCO (US NIH, U01 CA137088 and R01 CA059045), DALS (US NIH, R01 CA048998), Colo2&3 (US NIH, R01 CA060987), 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, P01 CA055075, UM1 CA167552, R01 137178 and P50 CA127003), MEC (US NIH, R37 CA054281, P01 CA033619 and R01 CA063464), NHS (US NIH, R01 137178, P50 CA127003 and P01 CA087969), OFCCR (US NIH, U01 CA074783), PMH (US NIH, R01 CA076366), PHS (US NIH, CA042182), VITAL (US NIH, K05 CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C and 268200764316C) and PLCO (US NIH, Z01 CP 010200, U01 HG004446 and U01 HG 004438). 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 (U01 CA097735), the Familial Colorectal Neoplasia Collaborative Group (U01 CA074799; USC), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), the Seattle Colorectal Cancer Family Registry (U01 CA074794) and the University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). The GWAS work was supported by a National Cancer Institute grant (U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. B.Z. is a recipient 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, Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), Association Anne de Bretagne Génétique and Ligue Régionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer scan, phs000207.v1.p1 and GWAS of Lung Cancer and Smoking, phs000093.v2.p2).

Author information

Author notes

    • Wei-Hua Jia
    •  & Ben Zhang

    These authors contributed equally to this work.

    • Yi-Xin Zeng
    •  & Wei Zheng

    These authors jointly directed this work.

Affiliations

  1. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.

    • Wei-Hua Jia
    • , Zefang Ren
    • , Zhi-Zhong Pan
    •  & Yi-Xin Zeng
  2. Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Ben Zhang
    • , Qiuyin Cai
    • , Jirong Long
    • , Jiajun Shi
    • , Wanqing Wen
    • , Gong Yang
    • , Ryan J Delahanty
    • , Xiao-Ou Shu
    •  & Wei Zheng
  3. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

    • Keitaro Matsuo
    •  & Satoyo Hosono
  4. Molecular Epidemiology Branch, National Cancer Center, Goyang-si, Korea.

    • Aesun Shin
  5. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yong-Bing Xiang
    • , Yu-Tang Gao
    •  & Hong-Lan Li
  6. Institute for Health Promotion, Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.

    • Sun Ha Jee
    • , Eun Jung Park
    •  & Jaeseong Jo
  7. Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, Korea.

    • Dong-Hyun Kim
    •  & Jin-Young Jeong
  8. Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Bu-Tian Ji
  9. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • Fumihiko Matsuda
  10. Center for Colorectal Cancer, National Cancer Center, Goyang-si, Korea.

    • Jae Hwan Oh
    •  & Ji Won Park
  11. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

    • Yoon-Ok Ahn
  12. Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.

    • Graham Casey
  13. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Ulrike Peters
  14. Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.

    • Ulrike Peters

Consortia

  1. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)

    A complete list of members is provided in the Acknowledgements.

  2. Colon Cancer Family Registry (CCFR)

    A complete list of members is provided in the Acknowledgements.

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Contributions

W.Z. conceived and directed ACCC as well as the Shanghai-Vanderbilt Colorectal Cancer Genetics Project. W.-H.J., Y.-X.Z., K.M., A.S., Y.-B.X., S.H.J., D.-H.K., U.P. and G.C. directed CRC projects at Guangzhou, Aichi, Korea-NCC, Shanghai, KCPS-II, Korea-Seoul, GECCO and CCFR, respectively. B.Z., Q.C. and W.W. coordinated the project. Q.C. directed laboratory operations. J.S. performed genotyping experiments. B.Z., J.L. and W.W. performed statistical analyses. W.Z. wrote the manuscript with substantial contributions from B.Z., Q.C., J.L., X.-O.S. and R.J.D. Z.R., G.Y., B.-T.J., Z.-Z.P., F.M., Y.-T.G., J.H.O., Y.-O.A., E.J.P., H.-L.L., J.W.P., J.J., J.-Y.J. and S.H. contributed to data and biological sample collection in the original studies included in ACCC and contributed to manuscript revision. Members of GECCO and CCFR contributed to data and biological sample collection in studies included in these consortia.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Wei Zheng.

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