Letter abstract

Nature Genetics 40, 623 - 630 (2008)
Published online: 30 March 2008 | Corrected online: 13 April 2008 | doi:10.1038/ng.111

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

Ian PM Tomlinson1,38, Emily Webb2, Luis Carvajal-Carmona1, Peter Broderick2, Kimberley Howarth1, Alan M Pittman2, Sarah Spain1, Steven Lubbe2, Axel Walther1, Kate Sullivan2, Emma Jaeger1, Sarah Fielding2, Andrew Rowan1, Jayaram Vijayakrishnan2, Enric Domingo1, Ian Chandler2, Zoe Kemp1, Mobshra Qureshi2, Susan M Farrington3, Albert Tenesa3, James GD Prendergast3, Rebecca A Barnetson3, Steven Penegar2, Ella Barclay1, Wendy Wood2, Lynn Martin1,4,5, Maggie Gorman1, Huw Thomas6, Julian Peto7,8, D Timothy Bishop9, Richard Gray10, Eamonn R Maher5, Anneke Lucassen11, David Kerr12, D Gareth R Evans4, The CORGI Consortium37, Clemens Schafmayer13,14, Stephan Buch16,17, Henry Völzke15, Jochen Hampe16, Stefan Schreiber14,17, Ulrich John15, Thibaud Koessler18, Paul Pharoah18, Tom van Wezel19, Hans Morreau19, Juul T Wijnen20, John L Hopper21, Melissa C Southey22, Graham G Giles21,23, Gianluca Severi23, Sergi Castellví-Bel24, Clara Ruiz-Ponte25, Angel Carracedo25, Antoni Castells24, The EPICOLON Consortium37, Asta Försti26,27, Kari Hemminki26,27, Pavel Vodicka28, Alessio Naccarati28, Lara Lipton29, Judy WC Ho30, K K Cheng30, Pak C Sham30, J Luk30, Jose AG Agúndez31, Jose M Ladero32, Miguel de la Hoya33, Trinidad Caldés33, Iina Niittymäki34, Sari Tuupanen34, Auli Karhu34, Lauri Aaltonen34, Jean-Baptiste Cazier35, Harry Campbell36,38, Malcolm G Dunlop3,38 & Richard S Houlston2,38

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To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10- 4 in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 times 10- 13 overall; P = 6.9 times 10- 12 replication), and rs16892766, at 8q23.3 (P = 3.3 times 10- 18 overall; P = 9.6 times 10- 17 replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

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  1. Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.
  2. Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK.
  3. Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
  4. Department of Medical Genetics, St Mary's Hospital, Manchester M13 0JH, UK.
  5. Department of Medical and Molecular Genetics, University of Birmingham School of Medicine and West Midlands Regional Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK.
  6. Family Cancer Clinic, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK.
  7. Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
  8. Cancer Research UK Epidemiology and Genetics Unit, Institute of Cancer Research, London SM2 5NG, UK.
  9. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
  10. Birmingham Clinical Trials Unit, University of Birmingham, Birmingham B15 2TA, UK.
  11. University of Southampton and Wessex Clinical Genetics Service, Mailpoint 105, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK.
  12. Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Oxford OX2 6HA, UK.
  13. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Arnold-Heller-Stras zlige 3, 24105 Kiel, Germany.
  14. POPGEN Biobank, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany.
  15. Department of Community Medicine and SHIP Biobank, University Hospital of the Ernst-Moritz-Arndt University, Walther Rathenau Str. 1, 17487 Greifswald, Germany.
  16. Department of General Internal Medicine, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany.
  17. Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany.
  18. Cancer Research United Kingdom Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
  19. Department of Pathology, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
  20. Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
  21. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston Street, Carlton VIC 3053, Australia.
  22. Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Grattan Street, Parkville VIC 3052, Australia.
  23. Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne Street, Carlton VIC 3053, Australia.
  24. Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBER-EHD, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
  25. Genomic Medicine Group, Fundacion Publica Galega de Medicina Xenomica (FPGMX), Spanish National Genotyping Center (CeGen)-USC, CIBERER, Hospital Clínico, Santiago de Compostela, Galicia, Spain.
  26. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
  27. Center for Family and Community Medicine, Karolinska Institute, 141 83 Huddinge, Sweden.
  28. Institute of Experimental Medicine at the Academy of Sciences, Czech Rep., Videnska 1083, 14200 Prague, Czech Republic.
  29. Department of Medical Oncology and Clinical Haematology, Western Hospital, Footscray 3011, Victoria, Australia.
  30. The University of Hong Kong, Hong Kong.
  31. Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
  32. Service of Gastroenterology, San Carlos University Hospital, Madrid, Spain.
  33. Molecular Oncology Laboratory, Hospital San Carlos, 28040 Madrid, Spain.
  34. Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
  35. Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.
  36. Public Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
  37. A full list of authors is provided in the Supplementary Note online.
  38. These authors contributed equally to this work.

Correspondence to: Richard S Houlston2,38 e-mail: richard.houlston@icr.ac.uk

Correspondence to: Ian PM Tomlinson1,38 e-mail: ian.tomlinson@cancer.org.uk

* In the version of this article initially published online, the name of the 71st author was misspelled. The correct author name is Sari Tuupanen. This error has been corrected in all versions of the article.

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