Abstract

Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2–4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1–4 of 1.18 (trend; P = 1.41 × 10−8) and 1.14 (trend; P = 1.32 × 10−5), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07–1.26; P = 5.05 × 10−4). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12–1.23; P = 3.16 × 10−11). This locus has also been implicated in prostate cancer1,2,3.

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Acknowledgements

The authors thank D. Daftary and T. Selander at the Mount Sinai Hospital Biorepository for technical and administrative assistance with OFCCR samples. We also are grateful to A. Bélisle, S. Roland, M.-C. Tessier and D. Vincent of the McGill University and Génome Québec Innovation Centre for technical genotyping assistance. We acknowledge all those involved in recruitment and assembly of the biological and data resources of the Colorectal Cancer Genetic Susceptibility (COGS) study and the Scottish Colorectal Cancer Study (SOCCS), including the Edinburgh Wellcome Trust Clinical Research Facility and also the Family Practitioner Services Department, the Cancer Intelligence Unit of the Information and Statistics Division (ISD) and Scottish Cancer Registry Cancer, all of the Scottish Central National Health Service (NHS). C. Bonithon-Kopp, A. Pariente, B. Nalet and J. Lafon (Group d'Etude des Adenomas) and members of the Association Nationale des Gastroenterologues des Hopitaux Généraux. For administrative assistance, we acknowledge L. Blahut (Cancer Care Ontario). We are grateful to the nursing, laboratory and office staff throughout Edinburgh, at the Wellcome Trust Clinical Research Facility and at the central Scottish NHS departments, including Cancer Registry and the Scottish Cancer Intelligence Unit of ISD. Cancer Care Ontario, as the host organization to the ARCTIC Genome Project, acknowledges that this Project was funded by Genome Canada through the Ontario Genomics Institute, by Génome Québec, the Ministère du Dévelopement Économique et Régional et de la Recherche du Québec and the Ontario Institute for Cancer Research (B.W.Z., T.J.H., C.M.T.G, S.G. and M.C.). This work was supported through collaboration and cooperative agreements with the Colon Cancer Family Registry and principal investigators supported by the US National Cancer Institute, US National Institutes of Health under RFA CA-95-011, including S.G. at the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA076783) and J.P. at the Seattle Colorectal Cancer Family Registry (U01 CA074794). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating institutions or investigators in the Colon Familial Registry, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the Colon CFR. This work was supported through collaboration and cooperative agreement with the Newfoundland Familial Colon Cancer Registry at the Memorial University of Newfoundland (B.Y., R.G., J.G.). The work in Scotland was supported by Cancer Research UK (C348/A3758, C48/A6361), the UK Medical Research Council (G0000657-53203) and the Scottish Executive Chief Scientist's Office (K/OPR/2/2/D333, CSO CZB/4/94) (M.D.) and by a Centre Grant from the Digestive Disorders Foundation (http://www.corecharity.org.uk). Support in France came from the French Ministry of Research, Fondation de France (S.O., C.B.P.), Projet Hospitalier de Researche Clinique (PHRC) AOM01-006 (G.T.), Ligue Nationale contre le Cancer (G.T.), Groupement des Enterprises Francaises dans la Lutte contre le Cancer (GEFLUC) (S.B.) and the European Commission (E.R.). Support is acknowledged from the National Program for Complex Data Structures (Canada) (R.K.) and the Centre for Applied Genomics (Toronto) (C.G.).

Author information

Affiliations

  1. Cancer Care Ontario, 620 University Avenue, Toronto, Ontario M5G 1L7, Canada.

    • Brent W Zanke
    • , Celia MT Greenwood
    • , Rafal Kustra
    • , Michelle Cotterchio
    • , John McLaughlin
    •  & Steven Gallinger
  2. The Ontario Institute for Cancer Research, 101 College St., Toronto M5G 2L7, Canada.

    • Brent W Zanke
    •  & Thomas J Hudson
  3. The University of Ottawa, Faculty of Medicine, Division of Hematology, 501 Smythe Road, Ottawa K1H 8L6, Canada.

    • Brent W Zanke
  4. Genetics and Genome Biology, Hospital for Sick Children, 15-703 TMDT East, 101 College Street, Toronto, Ontario M5G 1L7, Canada.

    • Celia MT Greenwood
    • , Jagadish Rangrej
    • , Theodore Chiang
    •  & Edgar Crowdy
  5. University of Toronto, Department of Public Health Sciences Health Sciences Building, 155 College Street, Toronto M5T 3M7, Canada.

    • Celia MT Greenwood
    • , Rafal Kustra
    •  & Michelle Cotterchio
  6. Colon Cancer Genetics Group, University of Edinburgh Cancer Research Centre and UK Medical Research Council (MRC) Human Genetics Unit, Western General Hospital, Edinburgh UK EH4 2XU, UK.

    • Albert Tenesa
    • , Susan M Farrington
    • , James Prendergast
    • , Harry Campbell
    •  & Malcolm G Dunlop
  7. INSERM U599, Institut Paoli Calmettes, F-13009 Marseille, France.

    • Sylviane Olschwang
  8. The McGill University and Genome Quebec Innovation Centre, 700 Dr. Penfield Ave., Montreal, Quebec H3G 1A4, Canada.

    • Vincent Ferretti
    • , Philippe Laflamme
    • , Saravanan Sundararajan
    • , Stéphanie Roumy
    • , Jean-François Olivier
    • , Frédérick Robidoux
    • , Robert Sladek
    • , Alexandre Montpetit
    •  & Thomas J Hudson
  9. Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, 600 University Ave., Toronto, Ontario M5G 1X5, Canada.

    • Peter Campbell
    • , Anne Marie O'Shea
    • , George Zogopoulos
    • , John McLaughlin
    •  & Steven Gallinger
  10. EA3823 and Institut des Maladies de l'Appareil Digestif (IMAD), Centre Hospitalier Universitaire Hotel-Dieu, 44093 Nantes Cedex 01, France.

    • Stephane Bezieau
    • , Bruno Buecher
    •  & Sebastien Kury
  11. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.

    • Polly Newcomb
    •  & John Potter
  12. Memorial University of Newfoundland, St. John's, Newfoundland A1C 5S7, Canada.

    • Ban Younghusband
    • , Roger Green
    •  & Jane Green
  13. Clinical Genetics Department, University of Edinburgh, Edinburgh EH4 2XU, UK.

    • Mary E M Porteous
  14. Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.

    • Harry Campbell
  15. Centre d'Etude du Polymorphisme Humain,27 rue Juliette Dodu, F-75010 Paris, France.

    • Helene Blanche
    • , Mourad Sahbatou
    •  & Emmanuel Tubacher
  16. Institut National de la Santé et de la Recherche Médicale (INSERM) U535, Hopital Paul Brousse, BP1000, 94800 Villejuif, France.

    • Catherine Bonaiti-Pellié
  17. Faculty of Medicine, Imperial College W2 1PG, London, UK.

    • Elio Riboli
  18. Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Department of Health and Human Services (DHHS), and Division of Cancer Genetics and Epidemiology, NCI, NIH, DHHS, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.

    • Stephen J Chanock
  19. Division of Cancer Epidemiology and Genetics National Cancer Institute 8717 Grovemont Circle, Bethesda, Maryland 20892-4605, USA.

    • Gilles Thomas

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Contributions

B.W.Z., C.M.T.G., R.K., S.G., M.C. and T.J.H. devised and executed the original study design and prepared this manuscript. J.R., A.T., S.M.F., J.P., S.O., T.C., E.C., V.F., P.L., S.S., S.R., J.-F.O., F.R. and A.M. assisted in data analysis. R.S., P.C., S.B., A.M.O., G.Z., M.J., J.M., B.Y., R.G., J.G., M.E.M.P., H.C., H.B., M.S., E.T., C.B.-P., B.B., E.R., S.K. and S.J.C. provided insights and G.T., M.G.D., J.P., P.N. and E.P. assisted in sample procurement and study design and interpretation. A.T., S.M.F., J. Prendergast, M.E.M.P., H.C. and M.G.D. designed and undertook stages 3 and 4 of the study using the Scottish sample and data resource and contributed to writing the manuscript.

Competing interests

B.W.Z. is the founder and equity holder of Arctic Dx, a new Canadian biotechnology company that has received a license in the field of diagnostics for intellectual property generated by several Canadian institutions involved in this research. Arctic Dx currently has no financiers or employees.

Corresponding author

Correspondence to Thomas J Hudson.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Table 1, Supplementary Table 3, Supplementary Table 4, Supplementary Figure 1, Supplementary Methods

Excel files

  1. 1.

    Supplementary Table 2

    Phase 2 validation genotyping at 76 sites.

  2. 2.

    Supplementary Table 5

    Selected SNPs genotyped using the Illumina GoldenGate Assay in stage 1 of the ARCTIC project.

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DOI

https://doi.org/10.1038/ng2089

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