MUTYH – Familial Adenomatous Polyposis 2

MUTYH-associated polyposis (MAP) is an autosomal recessive colorectal cancer syndrome caused by biallelic germline mutations in the MUTYH gene, predisposing to multiple adenomatous colonic polyps and early-onset carcinoma. Patients typically present between ages 30–55 with attenuated to classic polyposis (10–100 polyps) and an accelerated adenoma–carcinoma sequence. Extracolonic manifestations include duodenal adenomatosis, jejunal carcinoma, desmoid tumors, and cutaneous sebaceous neoplasms, reflecting tissue-specific oxidative DNA damage ([PMID:19404084]).

Genetically, >200 unrelated MAP patients harbor biallelic pathogenic variants, most frequently c.1187G>A (p.Gly396Asp) and c.536A>G (p.Tyr179Cys), in trans and compound heterozygous configurations, consistent with recessive inheritance ([PMID:18515411]). Segregation of homozygous frameshift alleles was demonstrated in consanguineous kindreds with concordant colonic and extracolonic phenotypes ([PMID:15690400]). Monoallelic carriers show a modest, but significant, increase in colorectal cancer risk (SIR 2.12), supporting carrier surveillance ([PMID:19394335]).

Functional assays reveal that MAP-associated missense variants abolish or markedly impair adenine DNA glycosylase activity toward 8-oxoguanine:A mismatches, leading to G:C→T:A transversion mutator phenotypes in vitro and in cell models ([PMID:11818965], [PMID:29915346]). The MUTYH C306W variant further disrupts [4Fe4S] cluster redox signalling and DNA binding, confirming redox-mediated repair as critical for genome stability ([PMID:29915346]). Mouse embryonic stem cells lacking Mutyh exhibit a 2-fold increase in spontaneous mutation rate, rescue of which depends on wild-type glycosylase function ([PMID:12917422]).

Limited conflicting data exist; somatic inactivation of MUTYH is rare in sporadic colorectal cancers, and monoallelic MUTYH mutations without polyposis are not associated with MAP phenotypes. No studies to date refute the recessive gene–disease relationship.

Overall, genetic and experimental evidence converges to a definitive association between biallelic MUTYH loss-of-function and MAP. Testing for the two common European founder alleles (p.Tyr179Cys, p.Gly396Asp) followed by full‐gene analysis in heterozygotes is recommended. MAP genetic diagnosis enables tailored surveillance (colonoscopy and small‐bowel screening), risk assessment for relatives, and informs prophylactic management.

Key Take-home: Biallelic MUTYH pathogenic variants cause an autosomal recessive polyposis syndrome with definitive clinical validity and well-characterized biochemical defects, supporting routine genetic testing in patients with multiple colorectal adenomas.

References

• Diseases of the Colon & Rectum • 2009 • Aggressive phenotype of MYH-associated polyposis with jejunal cancer and intra-abdominal desmoid tumor: report of a case. PMID:19404084
• Gut • 2008 • Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. PMID:18515411
• American Journal of Medical Genetics Part A • 2005 • A kindred with MYH-associated polyposis and pilomatricomas. PMID:15690400
• Gastroenterology • 2009 • Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. PMID:19394335
• Nature Genetics • 2002 • Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. PMID:11818965
• Nature Chemistry • 2018 • A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster. PMID:29915346
• The Journal of Biological Chemistry • 2003 • Mutator phenotype of MUTYH-null mouse embryonic stem cells. PMID:12917422

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