Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-Tumor Phenotype Including a Predisposition to Colon and Breast Cancer

Biallelic germline mutations affecting NTHL1 predispose to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown, which hampers patient recognition. We describe 29 individuals from 17 families, of which 26 developed one (n=10) or multiple (n=16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in women with biallelic NTHL1 mutations (60%). Mutational signature analysis of 14 tumors from seven organs revealed that deficient NTHL1 repair underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers, and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.