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A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

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Abstract

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10−10; odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83–0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77–0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10−8).

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Acknowledgments

The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

ASTERISK: We are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students.

CANCER PREVENTION STUDY II: CPS-II is supported by the American Cancer Society (ACS). We would like to thank the CPS-II participants and the CPS-II Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program.

DACHS: We thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance.

GECCO: The authors would like to thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. The authors also acknowledge COMPASS (Comprehensive Center for the Advancement of Scientific Strategies) at the Fred Hutchinson Cancer Research Center for their work harmonizing the GECCO epidemiological data set. The authors acknowledge Dave Duggan and team members at TGEN (Translational Genomics Research Institute), the Broad Institute, and the Génome Québec Innovation Center for genotyping DNA samples of cases and controls, and for scientific input for GECCO.

HPFS, NHS and PHS: We would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo and Amit Joshi who assisted in programming for NHS and HPFS, and Haiyan Zhang who assisted in programming for the PHS. We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

PLCO: The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O’Brien and staff, Westat, Inc., and Drs. Bill Kopp and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI.

PMH: The authors would like to thank the study participants and staff of the Hormones and Colon Cancer study.

WHI: The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf.

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    Authors and Affiliations

    1. Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada

      Mathieu Lemire, Syed H. E. Zaidi & Thomas J. Hudson

    2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

      Conghui Qu, Mengmeng Du, Tabitha A. Harrison, Li Hsu, Jihyoun Jeon, Polly A. Newcomb, John D. Potter, Emily White & Ulrike Peters

    3. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

      Lenora W. M. Loo, Hansong Wang & Loïc Le Marchand

    4. Occupational and Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA

      Sonja I. Berndt

    5. Service de Génétique Médicale, CHU Nantes, Nantes, France

      Stéphane Bézieau & Sébastien Küry

    6. EA 4273, Faculté de médecine, Université de Nantes, Nantes, France

      Stéphane Bézieau

    7. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

      Hermann Brenner & Michael Hoffmeister

    8. German Cancer Consortium (DKTK), Heidelberg, Germany

      Hermann Brenner

    9. Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

      Hermann Brenner

    10. American Cancer Society, Atlanta, GA, USA

      Peter T. Campbell & Eric J. Jacobs

    11. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

      Andrew T. Chan

    12. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA

      Andrew T. Chan

    13. Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

      Jenny Chang-Claude & Anja Rudolph

    14. Department of Preventive Medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

      Christopher K. Edlund, Fredrick R. Schumacher, Graham Casey & Stephen B. Gruber

    15. Samuel Lunenfeld Research Institute, Toronto, ON, M5S 1X5, Canada

      Steven Gallinger

    16. Division of General Surgery, Toronto General Hospital, Toronto, ON, M5G 2C4, Canada

      Steven Gallinger

    17. Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA

      Robert W. Haile

    18. Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia

      John L. Hopper, Mark A. Jenkins & Gianluca Severi

    19. Department of Preventive Medicine and The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

      Lifang Hou

    20. Department of Biostatistics, University of Washington, Seattle, WA, USA

      Li Hsu

    21. Case Comprehensive Cancer Center and Swetland Center for Environmental Health, Case Western Reserve University, Cleveland, OH, USA

      Li Li

    22. Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA

      Noralane M. Lindor

    23. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA

      Polly A. Newcomb, John D. Potter & Emily White

    24. Centre for Public Health Research, Massey University, Wellington, New Zealand

      John D. Potter

    25. Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel

      Gad Rennert

    26. Clalit Health Services National Cancer Control Center, Haifa, Israel

      Gad Rennert

    27. Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

      Gad Rennert

    28. Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

      Robert E. Schoen

    29. Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA

      Daniela Seminara

    30. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia

      Gianluca Severi

    31. Human Genetics Foundation (HuGeF), Turin, Italy

      Gianluca Severi

    32. Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA

      Martha L. Slattery

    33. Discipline of Genetics, Memorial University of Newfoundland, St. John’s, NF, A1B 3V6, Canada

      Michael O. Woods

    34. Cancer Care Ontario, University of Toronto, Toronto, ON, Canada

      Michelle Cotterchio

    35. Department of Medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

      Stephen B. Gruber

    36. School of Public Health, University of Washington, Seattle, WA, USA

      Ulrike Peters

    37. Department of Medical Biophysics, University of Toronto, Toronto, ON, M5S 1A1, Canada

      Thomas J. Hudson

    38. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A1, Canada

      Thomas J. Hudson

    Authors
    1. Mathieu Lemire
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    2. Conghui Qu
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    3. Lenora W. M. Loo
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    4. Syed H. E. Zaidi
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    5. Hansong Wang
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    6. Sonja I. Berndt
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    7. Stéphane Bézieau
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    8. Hermann Brenner
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    9. Peter T. Campbell
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    10. Andrew T. Chan
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    11. Jenny Chang-Claude
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    12. Mengmeng Du
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    13. Christopher K. Edlund
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    14. Steven Gallinger
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    15. Robert W. Haile
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    16. Tabitha A. Harrison
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    17. Michael Hoffmeister
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    18. John L. Hopper
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    19. Lifang Hou
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    20. Li Hsu
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    21. Eric J. Jacobs
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    22. Mark A. Jenkins
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    23. Jihyoun Jeon
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    24. Sébastien Küry
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    25. Li Li
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    26. Noralane M. Lindor
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    27. Polly A. Newcomb
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    28. John D. Potter
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    29. Gad Rennert
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    30. Anja Rudolph
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    31. Robert E. Schoen
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    32. Fredrick R. Schumacher
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    33. Daniela Seminara
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    34. Gianluca Severi
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    35. Martha L. Slattery
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    36. Emily White
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    37. Michael O. Woods
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    38. Michelle Cotterchio
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    39. Loïc Le Marchand
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    40. Graham Casey
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    41. Stephen B. Gruber
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    42. Ulrike Peters
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    43. Thomas J. Hudson
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    Corresponding author

    Correspondence to Mathieu Lemire.

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    Funding

    GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045).

    ASTERISK: a 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).

    CCFR: This work was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the following CCFR centers: Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (U01/U24 CA074794), USC Consortium Colorectal Cancer Family Registry U01/U24 CA074799). The Colon CFR GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01 CA122839 and R01 CA143237 to Graham Casey). CRC tumor and normal tissues used for the gene expression study were made available by The Jeremy Jass Memorial Pathology Bank. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR.

    COLO2&3: National Institutes of Health (R01 CA60987).

    CORECT: National Cancer Institute, National Institutes of Health under RFA# CA-09-002 (U19 CA148107). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in CORECT, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or CORECT.

    DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814).

    DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery); HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993 and P50 CA127003), NHS by the National Institutes of Health (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003,) and PHS by the National Institutes of Health (R01 CA042182).

    MEC: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464).

    OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation.

    PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007 May;39(5):645–9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep;41(9):986–90, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar;42(3):224–8), and the Lung Cancer and Smoking study (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009 Nov;85(5):679–91). The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping.

    PMH: National Institutes of Health (R01 CA076366 to P.A. Newcomb).

    VITAL: National Institutes of Health (K05 CA154337).

    WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

    Additional information

    M. Lemire and C. Qu contributed equally to this work.

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    Lemire, M., Qu, C., Loo, L.W.M. et al. A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1. Hum Genet 134, 1249–1262 (2015). https://doi.org/10.1007/s00439-015-1598-6

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