Human Genetics

, Volume 134, Issue 11–12, pp 1249–1262 | Cite as

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

  • Mathieu Lemire
  • Conghui Qu
  • Lenora W. M. Loo
  • Syed H. E. Zaidi
  • Hansong Wang
  • Sonja I. Berndt
  • Stéphane Bézieau
  • Hermann Brenner
  • Peter T. Campbell
  • Andrew T. Chan
  • Jenny Chang-Claude
  • Mengmeng Du
  • Christopher K. Edlund
  • Steven Gallinger
  • Robert W. Haile
  • Tabitha A. Harrison
  • Michael Hoffmeister
  • John L. Hopper
  • Lifang Hou
  • Li Hsu
  • Eric J. Jacobs
  • Mark A. Jenkins
  • Jihyoun Jeon
  • Sébastien Küry
  • Li Li
  • Noralane M. Lindor
  • Polly A. Newcomb
  • John D. Potter
  • Gad Rennert
  • Anja Rudolph
  • Robert E. Schoen
  • Fredrick R. Schumacher
  • Daniela Seminara
  • Gianluca Severi
  • Martha L. Slattery
  • Emily White
  • Michael O. Woods
  • Michelle Cotterchio
  • Loïc Le Marchand
  • Graham Casey
  • Stephen B. Gruber
  • Ulrike Peters
  • Thomas J. Hudson
Original Investigation

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).

Notes

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.

Compliance with ethical standards

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.

Supplementary material

439_2015_1598_MOESM1_ESM.docx (960 kb)
Supplementary material 1 (DOCX 959 kb)
439_2015_1598_MOESM2_ESM.xlsx (20 kb)
Supplementary material 2 (XLSX 20 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mathieu Lemire
    • 1
  • Conghui Qu
    • 2
  • Lenora W. M. Loo
    • 3
  • Syed H. E. Zaidi
    • 1
  • Hansong Wang
    • 3
  • Sonja I. Berndt
    • 4
  • Stéphane Bézieau
    • 5
    • 6
  • Hermann Brenner
    • 7
    • 8
    • 9
  • Peter T. Campbell
    • 10
  • Andrew T. Chan
    • 11
    • 12
  • Jenny Chang-Claude
    • 13
  • Mengmeng Du
    • 2
  • Christopher K. Edlund
    • 14
  • Steven Gallinger
    • 15
    • 16
  • Robert W. Haile
    • 17
  • Tabitha A. Harrison
    • 2
  • Michael Hoffmeister
    • 7
  • John L. Hopper
    • 18
  • Lifang Hou
    • 19
  • Li Hsu
    • 2
    • 20
  • Eric J. Jacobs
    • 10
  • Mark A. Jenkins
    • 18
  • Jihyoun Jeon
    • 2
  • Sébastien Küry
    • 5
  • Li Li
    • 21
  • Noralane M. Lindor
    • 22
  • Polly A. Newcomb
    • 2
    • 23
  • John D. Potter
    • 2
    • 23
    • 24
  • Gad Rennert
    • 25
    • 26
    • 27
  • Anja Rudolph
    • 13
  • Robert E. Schoen
    • 28
  • Fredrick R. Schumacher
    • 14
  • Daniela Seminara
    • 29
  • Gianluca Severi
    • 18
    • 30
    • 31
  • Martha L. Slattery
    • 32
  • Emily White
    • 2
    • 23
  • Michael O. Woods
    • 33
  • Michelle Cotterchio
    • 34
  • Loïc Le Marchand
    • 3
  • Graham Casey
    • 14
  • Stephen B. Gruber
    • 14
    • 35
  • Ulrike Peters
    • 2
    • 36
  • Thomas J. Hudson
    • 1
    • 37
    • 38
  1. 1.Ontario Institute for Cancer Research, MaRS CentreTorontoCanada
  2. 2.Public Health Sciences Division, Fred Hutchinson Cancer Research CenterSeattleUSA
  3. 3.Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluUSA
  4. 4.Occupational and Environmental Epidemiology BranchNational Cancer InstituteBethesdaUSA
  5. 5.Service de Génétique MédicaleCHU NantesNantesFrance
  6. 6.EA 4273, Faculté de médecineUniversité de NantesNantesFrance
  7. 7.Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
  8. 8.German Cancer Consortium (DKTK)HeidelbergGermany
  9. 9.Division of Preventive OncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  10. 10.American Cancer SocietyAtlantaUSA
  11. 11.Division of GastroenterologyMassachusetts General HospitalBostonUSA
  12. 12.Channing Division of Network MedicineBrigham and Women’s HospitalBostonUSA
  13. 13.Unit of Genetic Epidemiology, Division of Cancer EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  14. 14.Department of Preventive Medicine, Keck School of Medicine, USC Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  15. 15.Samuel Lunenfeld Research InstituteTorontoCanada
  16. 16.Division of General SurgeryToronto General HospitalTorontoCanada
  17. 17.Department of Medicine, Division of OncologyStanford UniversityStanfordUSA
  18. 18.Centre for Epidemiology and Biostatistics, School of Population and Global HealthThe University of MelbourneMelbourneAustralia
  19. 19.Department of Preventive Medicine and The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of MedicineNorthwestern UniversityEvanstonUSA
  20. 20.Department of BiostatisticsUniversity of WashingtonSeattleUSA
  21. 21.Case Comprehensive Cancer Center and Swetland Center for Environmental HealthCase Western Reserve UniversityClevelandUSA
  22. 22.Department of Health Sciences ResearchMayo ClinicScottsdaleUSA
  23. 23.Department of EpidemiologyUniversity of Washington School of Public HealthSeattleUSA
  24. 24.Centre for Public Health ResearchMassey UniversityWellingtonNew Zealand
  25. 25.Department of Community Medicine and EpidemiologyCarmel Medical CenterHaifaIsrael
  26. 26.Clalit Health Services National Cancer Control CenterHaifaIsrael
  27. 27.Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of TechnologyHaifaIsrael
  28. 28.Division of Gastroenterology, Hepatology, and NutritionUniversity of Pittsburgh Medical CenterPittsburghUSA
  29. 29.Division of Cancer Control and Population SciencesNational Cancer InstituteBethesdaUSA
  30. 30.Cancer Epidemiology Centre, Cancer Council VictoriaMelbourneAustralia
  31. 31.Human Genetics Foundation (HuGeF)TurinItaly
  32. 32.Department of Internal MedicineUniversity of Utah Health Sciences CenterSalt Lake CityUSA
  33. 33.Discipline of GeneticsMemorial University of NewfoundlandSt. John’sCanada
  34. 34.Cancer Care OntarioUniversity of TorontoTorontoCanada
  35. 35.Department of Medicine, Keck School of Medicine, USC Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  36. 36.School of Public HealthUniversity of WashingtonSeattleUSA
  37. 37.Department of Medical BiophysicsUniversity of TorontoTorontoCanada
  38. 38.Department of Molecular GeneticsUniversity of TorontoTorontoCanada

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