An oxidative mutational signature in normal tissues of a monoallelic MUTYH carrier

Biallelic loss of MUTYH causes MUTYH-associated polyposis (OMIM: 608456), characterized by the oxidative base-excision-repair mutational signature SBS18, but whether the roughly 1 in 100 individuals who carry a single pathogenic MUTYH allele acquire a mutational phenotype in normal tissue is unknown. Analysis of multi-tissue sequencing of 25 donors from the Somatic Mosaicism across Human Tissues (SMaHT) Network identified three heterozygous carriers of MUTYH p.Gly396Asp. One carrier showed SBS18 across multiple normal tissues, ranking first of 25 donors with three independent methods and remaining significant after adjustment for tissue, without a somatic, epigenetic or transcriptional second hit at the MUTYH locus. A single hypomorphic MUTYH allele can therefore leave a measurable oxidative mutational mark in healthy tissues, supporting tissue-level mutational readouts as an approach to cancer risk stratification within this common carrier state.