Journal
NATURE GENETICS
Volume 45, Issue 2, Pages 136-144Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2503
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Funding
- Cancer Research UK [C6199/A10417, C1298/A8362]
- Oxford NIHR Comprehensive Biomedical Research Centre
- Wellcome Trust [090532/Z/09/Z]
- John Fell Oxford University Press (OUP) Research Fund
- Junta de Extremadura, Spain (Consejeria de Economia, Comercio e Innovacion)
- European Union Seventh Framework Programme under FP7 collaborative project SYSCOL [FP7/207-2013, 258236]
- Bobby Moore Fund
- Biotechnology and Biological Sciences Research Council [BB/I02593X/1] Funding Source: researchfish
- Cancer Research UK [16459, 10589] Funding Source: researchfish
- Medical Research Council [MC_UP_A390_1107] Funding Source: researchfish
- National Institute for Health Research [03/DHCS/03/G121/51] Funding Source: researchfish
- BBSRC [BB/I02593X/1] Funding Source: UKRI
- MRC [MC_UP_A390_1107] Funding Source: UKRI
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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 E and 8 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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