NOVEL AND ESTABLISHED DNA REPAIR GENES IN POLYPOSIS SUSCEPTIBILITY

Familial adenomatous polyposis (FAP) is a relatively common syndrome predisposing to colorectal cancer, characterized by germline mutations in the APC gene. Up to 80% of patients with attenuated disease (AFAP, G, p.Ser1188Ter) in five polyposis families (PMID 30573798). Additionally, we found MSH2 variants in two AFAP cases. To address the contribution of defective DNA repair to mutation-negative polyposis cases, we scrutinized Finnish and South American cohorts with exome-wide (WES) and targeted methods. WES was conducted on 77 mutation-negative index cases and families with polyposis from the Helsinki University Hospital as well as nationwide Finnish and South American cancer registries. Variants common in the general population and predicted benign by in silico tools were excluded. Co-segregation and mutational signature analyses were conducted whenever possible. We identified possibly pathogenic mono-and biallelic germline mutations in 59,7% of the patients. Several DNA repair genes were affected, most notably: FANCM, MLH3, MSH2, MSH3, MUTYH, NTHL1, POLE and POLD1. An additional polyposis family carrying the MLH3 (c.3563C>G, p.Ser1188Ter) founder variant was discovered. Recurrent mutational signature 3 was present in MLH3-mutated cases. Our results suggest that germline alterations in established and novel predisposition genes contributing to DNA repair may be present in a significant proportion of molecularly unexplained familial adenomatous polyposis cases.