Oxidative mutational footprint emerges in normal tissue from a monoallelic MUTYH carrier
A single pathogenic allele can leave a molecular trace outside the tumor setting. In a multi-tissue analysis drawn from 25 donors in the Somatic Mosaicism across Human Tissues Network, investigators identified three heterozygous carriers of MUTYH p.Gly396Asp and found one individual with a clear SBS18 oxidative mutational signature across multiple normal tissues.
The finding matters because MUTYH has long been linked to cancer biology through its role in oxidative base-excision repair. Biallelic loss causes MUTYH-associated polyposis, a recognized hereditary cancer syndrome defined by accumulation of the SBS18 mutational pattern. Until now, whether people carrying just one pathogenic allele develop any measurable mutational phenotype in healthy tissue remained unresolved.
Here, the answer is yes in at least one carrier.
A normal-tissue signal without an obvious second hit
The strongest result came from a carrier whose tissues ranked first among all 25 donors for SBS18 burden when analyzed by three independent methods. The signal remained significant after adjustment for tissue, which argues against the pattern being a simple artifact of sampling one organ or one cell type more heavily than another. Equally striking, no somatic, epigenetic, or transcriptional second hit at the MUTYH locus was identified.
That absence is biologically important. Classic tumor suppressor logic often depends on two-step inactivation, but this case suggests that a single hypomorphic allele may be enough to shift the repair balance in a way that becomes visible in normal tissue. Oxidative base-excision repair is a continual housekeeping process; when the pathway is partially compromised, oxidative lesions can accumulate and leave behind a mutational signature even before neoplasia appears.
The implication is direct: inherited risk may sometimes be readable in the tissue itself, not only inferred from genotype.
Why SBS18 in healthy tissue changes the conversation
SBS18 is the molecular scar associated with oxidative DNA damage. In practical terms, it reflects the cumulative effect of repair failure when the genome is repeatedly exposed to reactive oxygen species generated by normal metabolism and environmental stress. In a fully competent repair system, these lesions are corrected before they become permanent sequence changes. In a partially impaired state, some damage survives replication and becomes fixed as a mutation.
This preprint places that biology in human normal tissue rather than in a tumor sample. That distinction is critical for risk stratification. If a carrier state can be accompanied by a measurable mutational burden in healthy tissue, then germline status may not be the whole story; tissue-level readouts could provide a more immediate estimate of whether the inherited variant is exerting a functional effect.
One carrier showed the signal. Two did not.
That uneven distribution is the most clinically interesting part of the dataset. It suggests incomplete penetrance at the level of mutational phenotype, even among people who share the same pathogenic allele. Some carriers may maintain enough repair capacity to avoid a detectable footprint, while others show a measurable oxidative signature in multiple tissues. For clinicians and genetic counselors, this raises the possibility that monoallelic MUTYH status is not a binary biological state.
What the data support, and what they do not
The study is narrow, but the biological message is strong. Among 25 donors, three carried MUTYH p.Gly396Asp in the heterozygous state. One of those carriers showed SBS18 across multiple normal tissues and ranked first across the cohort by three separate analytic methods. The signal persisted after tissue adjustment and was not accompanied by an identifiable second hit at the MUTYH locus at the somatic, epigenetic, or transcriptional level.
What the analysis does not yet establish is clinical prognosis. The abstract does not provide cancer incidence, longitudinal follow-up, organ-specific risk estimates, or thresholds that would let a clinician translate this signature into surveillance decisions. It also does not claim that every monoallelic carrier will show the same phenotype, only that a single hypomorphic allele can leave a measurable oxidative mark in healthy tissue.
Even so, the concept has weight. Hereditary cancer assessment has relied heavily on inherited variant classification and family history. This work points toward a more functional layer: a mutational readout in normal tissue that could, in principle, separate carriers whose allele is merely present from those in whom it is biologically active at the tissue level.
A functional biomarker for a common carrier state
Monoallelic MUTYH carrier status is common, roughly affecting 1 in 100 individuals. That prevalence makes the question more than academic. A subtle defect in oxidative repair across a large population could matter if it marks a subgroup with increased vulnerability to mutation accumulation over time.
The preprint positions tissue sequencing as a potential tool for cancer risk stratification in this setting. The logic is straightforward: if the repair defect is measurable in healthy tissue, then it may serve as an intermediate biomarker linking genotype to downstream malignant risk. Such a marker would be especially useful when genotype alone does not capture functional impact, or when additional modifiers determine whether a carrier actually accrues a mutational phenotype.
For now, the data support a cautious reading. A single carrier demonstrated the expected oxidative signature in normal tissues, and the observation was robust enough to survive multiple analytic approaches. The finding expands the biological reach of MUTYH beyond the classic biallelic disease model and suggests that even one pathogenic allele can matter at the level of somatic mutation accumulation.
The next question is not whether oxidative repair matters in MUTYH biology. It is how often this tissue-level signal appears in monoallelic carriers, in which organs it is strongest, and whether it can be tied to future cancer risk with enough precision to guide care.