Abstract
Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.
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Change history
08 May 2013
In the version of this article initially published, the name of author Estrella Guarino was incorrectly listed as Estrella Guarino Almeida. The error has been corrected in the HTML and PDF versions of this article.
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Acknowledgements
We are grateful to all the affected individuals and their relatives in the families studied and to those who have provided their medical care. We acknowledge the help of many colleagues who are part of the teams who work on the CORGI study. We acknowledge the use of DNA from the British 1958 Birth Cohort collection. This work was principally funded by Cancer Research UK (C6199/A10417) and the Oxford NIHR Comprehensive Biomedical Research Centre (to I.T.). We also acknowledge core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). Work in the laboratory of R.S.H. is supported by funding from Cancer Research UK (C1298/A8362, supported by the Bobby Moore Fund). Work in the laboratory of S.E.K. was supported by project grants from Cancer Research UK and the John Fell Oxford University Press (OUP) Research Fund. We thank O. Fleck (University of Copenhagen) for fission yeast strains. I.S. is supported by a fellowship from the Junta de Extremadura, Spain (Consejería de Economía, Comercio e Innovación). R.S.H. and I.T. acknowledge funding from the European Union Seventh Framework Programme (FP7/207-2013) under grant 258236, FP7 collaborative project SYSCOL.
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C. Palles, K.M.H., E.D., A.M.J., P.B., A.S., D.C., Z.K., S.L.S., C. Petridis, E.J.S., L.G.C.-C., Y.M., K.K., S.D., E.G., I.S. and S.H. performed laboratory experiments and/or analyzed the data. J.-B.C. analyzed whole-genome sequencing data, with assistance from M.B.K., and supervised other bioinformatics data analysis. J.T., S.E.K. and I.T. supervised laboratory experiments. G.M., P.D. and D.B. oversaw WGS500 analysis, and C.C.H. provided additional statistical advice. L.M., E.B., M.G., A.L., C. Petridis, R.R., E.J.S., D.J.K., S.C., H.J.W.T., R.S.H. and I.T. obtained samples. J.G. undertook structural analysis. R.S.H. and I.T. provided sequencing data and oversaw the study. I.T. wrote the manuscript.
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Palles, C., Cazier, JB., Howarth, K. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45, 136–144 (2013). https://doi.org/10.1038/ng.2503
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DOI: https://doi.org/10.1038/ng.2503
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