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A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk

Abstract

To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-β and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (Ptrend = 1.0 × 10−12).

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Figure 1: The SMAD7 locus.

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Acknowledgements

We are very grateful to the following: all individuals assessed in the study; colleagues at UK Clinical Genetics Centres and the National Cancer Research Network. Cancer Research UK provided principal funding for this study. Additional funding was provided by CORE, the European Union (CPRB LSHC-CT-2004-503465) 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.

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R.S.H. and I.T. designed the study and obtained financial support. R.S.H. and I.T. drafted the manuscript, with substantial contributions from E.W. and A.M.P. Z.K., W.W., E.B., S.P., E.P., D.K., R.G., J.P., R.S.H., I.T. and members of the CORGI Consortium (see Supplementary Note) developed patient and sample acquisition; W.W., S.P., E.B., M.G. and L.M. performed sample collection; P.B., K.G., S.S., S.L., K.S., J.V., M.Q. and S.F. performed sample preparation; S.L. performed microsatellite evaluation of tumors; P.B., Z.K., L.C.-C., A.M.P., S.S. and E.J. performed co-ordination of genotyping; P.B., L.C.-C., A.M.P., S.S., K.H., K.S., J.V. and S.F. performed genotyping; A.M.P. and S.L. performed re-sequencing and analysis of the SMAD7 locus; E.W. and J.-B.C. performed bioinformatics and statistical analyses; I.C. performed histology; and A.R. performed expression studies. All authors contributed to the final paper.

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Correspondence to Ian Tomlinson or Richard S Houlston.

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

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Supplementary Methods, Supplementary Tables 1–5, Supplementary Note (PDF 106 kb)

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Broderick, P., Carvajal-Carmona, L., Pittman, A. et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39, 1315–1317 (2007). https://doi.org/10.1038/ng.2007.18

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