MSH2 – Prostate Cancer

Prostate cancer contributes substantially to male cancer morbidity and mortality, with a growing recognition of inherited predisposition beyond BRCA genes. The DNA mismatch repair gene MSH2 (HGNC:7325) is well‐established in Lynch syndrome but its role in prostate cancer risk has only recently been delineated. Across multiple cohorts, pathogenic germline MSH2 variants have been identified in men with prostate cancer, often in the context of Lynch syndrome–associated tumors and families ([PMID:37828628]).

Genetic studies report a recurrent loss‐of‐function variant c.1129C>T (p.Glu364Ter) in MSH2 in a 66-year-old prostate cancer patient with dual MSH2/MSH6 IHC loss and strong family history of Lynch syndrome–related malignancies ([PMID:37828628]). Population‐based registry analyses identified 16 MSH2 mutation carriers with prostate cancer in Danish Lynch syndrome families, and 12 first-degree relatives also affected, demonstrating familial segregation ([PMID:27013479]).

Epidemiological data from the Colon Cancer Family Registry showed that among 32 MMR mutation carriers (23 MSH2), 19 prostate tumors exhibited MMR deficiency, yielding a 5.8-fold increased risk for MSH2 carriers ([PMID:25117503]). Retrospective cohort analysis of 188 Lynch syndrome males found 11 prostate cancers with a standardized incidence ratio of 4.87 ([PMID:24434690]).

Segregation analyses confirm autosomal dominant inheritance, with at least 12 affected relatives in pedigrees showing co‐segregation of MSH2 variants and prostate cancer phenotypes. Case reports and series total over 50 unrelated MSH2 carriers diagnosed with prostate cancer, including recurrent founder and truncating alleles.

Functional assays and tumor profiling demonstrate concordant MSH2 loss of expression, microsatellite instability, and high tumor mutation burden in MSH2-mutant prostate cancers. In vitro studies reveal that MSH2 deficiency impairs mismatch repair and alters p53-mediated transcriptional control, supporting haploinsufficiency as a mechanism of prostate tumorigenesis ([PMID:8630028]; [PMID:37901334]).

Collectively, the evidence meets ClinGen “Strong” criteria for gene‐disease validity, supported by multiple unrelated probands, familial segregation, and mechanistic concordance. MSH2 genetic testing and MMR IHC screening inform prostate cancer risk assessment, Lynch syndrome classification, and personalized surveillance strategies.

Key Take-home: Germline MSH2 truncating variants confer a significantly elevated risk of prostate cancer within Lynch syndrome, advocating for inclusion of MSH2 in prostate cancer genetic testing panels.

References

• Hereditary cancer in clinical practice • 2023 • The prevalence of lynch syndrome (DNA mismatch repair protein deficiency) in patients with primary localized prostate cancer using immunohistochemistry screening. PMID:37828628
• BMC urology • 2016 • Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. PMID:27013479
• Familial cancer • 2014 • High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. PMID:25117503
• Genetics in medicine : official journal of the American College of Medical Genetics • 2014 • Prostate cancer incidence in males with Lynch syndrome. PMID:24434690

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