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

A single heterozygous carrier of MUTYH p.Gly396Asp shows SBS18 across multiple normal tissues, ranking first among 25 SMaHT donors.

• Why it matters: It is unclear whether common monoallelic MUTYH carriers develop an oxidative mutational phenotype in healthy tissue, despite SBS18 being linked to biallelic MUTYH loss.
• What they did: Multi-tissue sequencing from 25 SMaHT donors identified three heterozygous carriers; one was assessed with three independent methods for SBS18 and checked for second-hit evidence at the MUTYH locus.
• The result: SBS18 persisted after adjustment for tissue and showed no somatic, epigenetic, or transcriptional second hit, implying tissue-level mutational readouts may support cancer risk stratification in this carrier state.

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