Enrichment Of Germline Dna-Repair Gene Mutations In Patients With Colorectal Cancer.

1500Background: Twin studies showed that 30% of all colorectal cancer (CRC) patients have an inherited genetic susceptibility. Several CRC predisposition genes have been described to date. However, mutations in these genes explain the risk in only 5-10% of CRC cases. In this study, we hypothesized that some of the CRC heritability may be explained by excess disruptive germline mutations in DNA repair genes (DRGs). Methods: Exome sequencing data of 716 in the discovery cohort (CanSeq and NHS/HPFS studies) and 1609 CRC patients in the validation cohort (TCGA and NSCCG studies) were used to evaluate germline variants in a pre-selected group of 42 DRGs and 12 known CRC risk genes. Frequencies of disruptive mutations in our cohorts were examined relative to 27173 non-Finnish European cancer-free adults from the ExAC cohort to evaluate for enrichment. Results: Of 716 patients in the discovery cohort, 27 (3.8%) patients harbored germline mutations in APC (n = 11), MSH6 (n = 2), MUTYH (n = 11), CHEK2 (n = 1) and ...