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Some families with many bowel polyps and early cancers have an inherited fault in the part of the copying machinery that checks its own work. The tumours end up with enormous numbers of mutations but normal-looking repeat sequences.
Whole-genome sequencing, supplemented by linkage and association analysis, identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and early-onset colorectal cancer cases but in no controls. The susceptibility variants, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. Both map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases epsilon and delta and are predicted to prevent correction of mispaired bases inserted during replication. Tumours from carriers were microsatellite stable but accumulated base substitutions, as confirmed by yeast functional assays; the authors noted that the hypermutant, microsatellite-stable colorectal cancers described shortly before were likely caused by somatic exonuclease-domain POLE mutations.
POLE and POLD1 are now on polyposis and colorectal germline panels, and the paper explains why a patient with many adenomas and an entirely normal mismatch repair panel still needs sequencing.
Shares POLE ultramutation (POLEmut), POLE, Oxford Cancer (Oxford University Hospitals and University of Oxford), DNA replication stress.
Shares Nature Genetics, Hereditary cancer syndromes, Germline vs somatic mutations, Germline (hereditary) testing.
Shares Nature Genetics, Whole-exome & whole-genome sequencing, Colorectal cancer.
Shares Germline vs somatic mutations, Tumour mutational burden (TMB), Whole-exome & whole-genome sequencing, Colorectal cancer.
Shares DNA replication stress, DNA damage response & homologous recombination.
Shares Germline vs somatic mutations, Whole-exome & whole-genome sequencing, Germline (hereditary) testing.
Shares Hereditary cancer syndromes, Whole-exome & whole-genome sequencing, Germline (hereditary) testing.
Shares Hereditary cancer syndromes, Germline (hereditary) testing.