MUTYH-Associated Polyposis: Recessive Base-Excision-Repair Risk
MUTYH encodes a DNA glycosylase in the base excision repair pathway that removes adenine mispaired with 8-oxoguanine, a common oxidative lesion. Biallelic pathogenic variants cause MUTYH-associated polyposis, an autosomal recessive predisposition to colorectal adenomas and cancer. The recessive inheritance pattern makes interpretation of one-versus-two variant results important.
Quick Answer
MUTYH encodes a DNA glycosylase in the base excision repair pathway that removes adenine mispaired with 8-oxoguanine, a common oxidative lesion. Biallelic pathogenic variants cause MUTYH-associated polyposis, an autosomal recessive predisposition to colorectal adenomas and cancer. The recessive inheritance pattern makes interpretation of one-versus-two variant results important.
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DNA Repair and Genomic Instability
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Reactive oxygen species convert guanine to 8-oxoguanine, which pairs readily with adenine during replication. If uncorrected, this produces G:C to T:A transversions. MUTYH excises the mispaired adenine so that repair synthesis can restore the correct base.
When MUTYH function is lost on both alleles, G:C to T:A transversions accumulate, including recurrent hits in the APC and KRAS genes that promote adenoma formation. The tumour spectrum overlaps with familial adenomatous polyposis but the polyp count is usually lower.
Recessive Inheritance and Result Interpretation
MUTYH-associated polyposis requires two pathogenic variants, one inherited from each parent. Carriers of a single pathogenic variant do not have the syndrome, though whether monoallelic carriers have a modestly increased colorectal risk has been studied and remains a topic of ongoing evaluation.
A report listing one MUTYH pathogenic variant plus a variant of uncertain significance cannot be assumed to be biallelic disease; laboratory follow-up on the uncertain variant and clinical correlation are needed.
How It Is Distinguished From Other Polyposis Syndromes
APC-related familial adenomatous polyposis is dominant and typically produces hundreds to thousands of polyps. Lynch syndrome is caused by mismatch-repair gene loss and produces mismatch-repair-deficient tumours. MUTYH-associated polyposis is recessive, generally causes tens of polyps, and tumours are usually mismatch-repair proficient.
Because presentations overlap, multigene panel testing that includes APC, MUTYH and the mismatch-repair genes is commonly used when an adenomatous polyposis phenotype is identified.
Surveillance and Management Implications
A confirmed biallelic diagnosis changes surveillance rather than drug treatment: colonoscopy at shorter intervals from early adulthood, upper gastrointestinal endoscopy because of duodenal polyp risk, and awareness of the smaller increased risks of some other cancers. Polyp burden usually stays manageable endoscopically, but a heavy or advanced burden can prompt colectomy.
Because inheritance is recessive, cascade testing focuses on a partner's carrier status when future children are the question, and on siblings, who each have a one-in-four chance of also being biallelic. Monoallelic relatives are common, and their care follows general population or family-history-adjusted guidance rather than the full syndrome protocol.
Key Takeaways
- ·MUTYH-associated polyposis is autosomal recessive and needs two pathogenic variants.
- ·Loss of this base-excision-repair glycosylase drives G:C to T:A transversions in APC and KRAS.
- ·A single MUTYH variant does not establish the syndrome; uncertain variants need laboratory follow-up.
Frequently asked questions
Do I have MUTYH-associated polyposis if one MUTYH variant was found?
No. The syndrome is autosomal recessive and requires two pathogenic variants, one on each copy of the gene. A single pathogenic variant plus a variant of uncertain significance is not confirmed biallelic disease until the uncertain variant is resolved.
How is it told apart from familial adenomatous polyposis?
APC-related polyposis is dominant and usually produces hundreds to thousands of polyps; MUTYH-associated polyposis is recessive, typically causes tens of polyps, and the tumours are usually mismatch-repair proficient.
What mutation pattern does MUTYH loss create?
An excess of G:C to T:A transversions, reflecting unrepaired 8-oxoguanine, including recurrent hits in APC and KRAS that drive adenoma formation.
References
- 1MUTYH, the base excision repair gene family member associated with colorectal cancer polyposis. Gastroenterol Hepatol Bed Bench, 2013. PubMed
- 2Base excision repair, the redox environment and therapeutic implications. Curr Mol Pharmacol, 2012. PubMed
- 3Role of POLE and POLD1 in familial cancer. Genet Med, 2020. PubMed
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