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

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Abstract

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 × 10−13 overall; P = 6.9 × 10−12 replication), and rs16892766, at 8q23.3 (P = 3.3 × 10−18 overall; P = 9.6 × 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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Figure 1: Summary of association results for rs16892766 and rs10795668.
Figure 2: The 8q23.3 locus.
Figure 3: The 10p14 locus.

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Change history

  • 13 April 2008

    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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Acknowledgements

Cancer Research UK provided principal funding for this study. We would like to thank all the individuals that participated in this study. We are grateful to colleagues at UK Clinical Genetics Centres and the UK National Cancer Research Network.

Institute of Cancer Research: Additional funding was provided by the European Union (CPRB LSHC-CT-2004-503465), CORE and the Thomas Falknor Fund. P.B. was funded by Leukaemia Research, and I.C. was in receipt of a clinical training fellowship from St. George's Hospital Medical School.

London Institute: Additional funding was provided by CORE and the Bobby Moore Fund.

Barcelona: We are sincerely grateful to all the individuals participating in this study who were recruited in 25 Spanish hospitals as part of the EPICOLON project. This work was supported by grants from the Fondo de Investigación Sanitaria (03/0070, 05/0071 and 05/2031), the Ministerio de Educación y Ciencia (SAF 04-07190 and 07-64873), the Asociación Española contra el Cáncer, Merck, the Xunta de Galicia (PGIDIT07PXIB9101209PR) and Fundación de Investigación Médica Mútua Madrileña (C.R.-P.). S.C.-B. is supported by a contract from the Fondo de Investigación Sanitaria (CP 03-0070, Ministerio de Sanidad).

Cambridge: SEARCH is funded by Cancer Research UK. P.D.P.P. is a CR-UK Senior Clinical Research Fellow; T.K. is funded by the Fondation Dr Henri Dubois-Ferriere Dinu Lipatti.

Edinburgh: The work was supported by Cancer Research UK (C348/A3758 and A8896, C48/A6361), Medical Research Council (G0000657-53203), Scottish Executive Chief Scientist's Office (K/OPR/2/2/D333, CZB/4/94) and centre grant from CORE as part of the Digestive Cancer Campaign. J.P. was funded by an MRC PhD studentship. We gratefully acknowledge the work of the COGS and SOCCS administrative teams, R. Cetnarskyj and the research nurse teams, all who recruited to the studies, the Wellcome Trust Clinical Research Facility for sample preparation and all clinicians and pathologists in NGS Scotland who made the work possible.

Extremadura: Work was supported by grants FIS 051056 from Instituto de Salud Carlos III, Madrid, Spain and FUNDESALUD, Mérida, Spain.

Finland: This work was supported by grants from Academy of Finland (Finnish Centre of Excellence Program 2006-2011), the Finnish Cancer Society, the Sigrid Juselius Foundation and the European Commission (9LSHG-CT-2004-512142).

Heidelberg: This study was supported by Deutsche Krebshilfe and the Swedish Cancer Society.

Kiel: This study was supported by the German Ministry of Education and Research through the National Genome Research Network through the POPGEN biobank project (01GS0426, 01GR0468) and the Medical Faculty Kiel. The SHIP recuitment project is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania.

Leiden: DFCCS was supported by Dutch Cancer Society grant UL2005-3247 and approved by the local Medical Ethical Committee (protocol P01.019); samples were handled according to Code Proper Secondary Use of Human Tissue by the Dutch Federation of Medical Sciences.

Madrid: Work was supported by the Fondo de Investigación Sanitaria (PI070316 and RD06/0020/0021).

Melbourne: The Melbourne Collaborative Cohort Study is supported by National Health and Medical Research Council (NHMRC) grants 209057, 251533 and 396414 and receives core funding and infrastructure support from The Cancer Council Victoria. J.L.H. is an NHMRC Australia Fellow and M.C.S. is an NHMRC Senior Research Fellow. We would like to acknowledge F. Odefrey for performing the genotyping.

Prague: This study was supported by the grant GACR 310/07/1430.

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Contributions

R.H. and I.T. designed the study and obtained financial support. The manuscript was drafted by R.H., I.T. and E.W., with substantial contributions from L.C.-C. and A.P. Statistical analyses were conducted primarily by E.W.

Institute of Cancer Research: Recruitment of affected individuals and acquisition of samples were undertaken by S.P., W.W., J.P., R.G. and members of the NSCCG. Sample preparation was performed by P.B., A.P., M.Q., K.S., S.F., J.V. and S.L. Histology review was done by I.C. Testing of MSI was performed by S.L. and I.C. Genotyping was performed and coordinated by P.B., S.F., J.V., K.S. and A.P. E.W. performed statistical analyses. E.W. and A.P. performed bioinformatic analyses.

London Institute: Recruitment of affected individuals and acquisition of samples were undertaken by Z.K., E.B., M.G., L.M., H.T., T.B., G.E., E.M., A.L. and members of the CORGI Consortium (D.R.G., A.L., T.B., E.R.M. and H.T.). Sample preparation was done by K.H., S.S., E.J., A.R. and Z.K. Genotyping was performed and coordinated by L.C.-C., K. Howarth, A.P., S. Spain, A.W., E.J., A.R., Z.K. and E.D. J.-B.C. performed bioinformatic and statistical analyses.

Barcelona: Recruitment of affected individuals and acquisition of samples were undertaken by S.C.-B., C.R.-P., A. Carracedo, A. Castells and members of the EPICOLON Consortium. Sample preparation was performed by S.C.-B., C.R.-P., A. Carracedo and A. Castells. Genotyping was performed and coordinated by S.C.-B., C.R.-P., A. Carracedo and A. Castells.

Leiden: Recruitment of affected individuals and acquisition of samples were undertaken by H.M.; sample preparation was performed by J.T.W. and T.V.W.; genotyping was performed and coordinated by J.T.W. and T.V.W.

Edinburgh: M.G.D. and H.C. designed the work in Scotland and obtained financial support. S.M.F., A.T., R.A.B. and J.D.G.P. contributed substantially to genotyping of Scottish sample set and to analysis of resultant data from Scotland.

Melbourne: G.G.G. and J.L.H. designed the Melbourne Collaborative Cohort Study and obtained financial support. G.G.G., J.L.H., M.C.S. and G.S. recruited affected individuals and acquired samples. Sample preparation was supervised by M.C.S. Genotyping was coordinated by M.C.S. and G.S.

Finland: I.N., S.T., A.K. and L.A.A. provided the Helsinki cohort with information on tumor site, microsatellite instability, family history and survival, as well as selected controls matched within the population.

Kiel: C.S., S.B. and J.H. performed and supervised the recruitment and phenotyping in Kiel; H.V. participated in the SHIP project and represents the Greifswald contribution.

Cambridge: Genotyping was undertaken by T.K. under the supervision of P.P.

All authors are members of the colorectal cancer association study consortium (CRACAC), and all authors contributed to the final paper.

Corresponding authors

Correspondence to Ian PM Tomlinson or Richard S Houlston.

Additional information

A full list of authors is provided in the Supplementary Note.

A full list of authors is provided in the Supplementary Note.

Supplementary information

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Supplementary Figure 1, Supplementary Tables 1–6, Supplementary Note (PDF 366 kb)

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Tomlinson, I., Webb, E., Carvajal-Carmona, L. et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40, 623–630 (2008). https://doi.org/10.1038/ng.111

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