MSH2 – Ovarian Cancer

MSH2, a core DNA mismatch repair (MMR) gene, is implicated in increased ovarian cancer risk within Lynch syndrome families. Carriers of pathogenic MSH2 variants exhibit a substantially elevated standardized incidence ratio for ovarian cancer (SIR 18.81; 95% CI 3.88–54.95) compared to the general population (PMID:22331944). This risk is part of a broader tumor spectrum encompassing colorectal, endometrial, and other Lynch‐associated cancers.

Germline MSH2 mutations confer an autosomal dominant inheritance pattern, with co‐segregation of variants and disease reported across multiple unrelated families. In a population‐based series of 63 Lynch syndrome–associated ovarian cancers, 49% harbored MSH2 mutations with consistent loss of MSH2 protein in tumor tissue, supporting familial segregation (PMID:21388660).

Case reports and series describe a spectrum of variant classes in MSH2, including truncating, splice‐site, and missense changes. One recurrent missense allele identified by multi‐gene panel testing in ovarian and breast cancer patients is c.1787A>G (p.Asn596Ser), which has been classified as deleterious on the basis of co‐occurrence with Lynch syndrome features (PMID:34371384).

Functional assays demonstrate that MSH2 interacts directly with p53 to regulate hMSH2 promoter activity, linking DNA damage responses to MMR gene expression (PMID:8630028). Msh2‐null mice show impaired apoptosis and increased mutation frequency in intestinal epithelium following alkylating agent exposure, recapitulating human MMR deficiency and tumor predisposition (PMID:10097137).

Universal tumor screening strategies combining MMR immunohistochemistry and microsatellite instability testing yield high sensitivity (92.3%) and specificity (97.7%) for Lynch syndrome detection in ovarian cancer patients, underscoring the clinical utility of reflex testing to guide germline analysis (PMID:32809219).

Integration of genetic and functional data supports a Strong clinical validity classification for MSH2 in ovarian cancer predisposition. Identifying MSH2 mutation carriers enables targeted surveillance, risk‐reducing interventions, and informed therapy selection.

Key Take‐home: MSH2 pathogenic variants drive autosomal dominant ovarian cancer risk in Lynch syndrome with robust segregation and functional evidence, warranting universal tumor‐based screening.

References

• Journal of clinical oncology • 2012 • Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. PMID:22331944
• Gynecologic oncology • 2011 • Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. PMID:21388660
• Biochemical and biophysical research communications • 1996 • Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2. PMID:8630028
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. PMID:10097137
• Cancer • 2020 • Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer. PMID:32809219

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