Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas: Mutational signature associated with MUTYH deficiency in cancers

Germlinealterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair(BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYHmutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signature also presenting germline MUTYHmutations. Altogether, these findings demonstrate that MUTYHinactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instabilityin new cancer types.