MSH6 – Lynch syndrome–associated Ovarian Cancer

MSH6 is a DNA mismatch repair gene whose germline variants cause Lynch syndrome and confer elevated ovarian cancer risk. Carriers of pathogenic MSH6 alleles develop ovarian carcinoma, often at early stages and with non-serous histology, reflecting dominant inheritance and high penetrance in affected kindreds. Clinical testing for MSH6 should be integrated into genetic evaluation of ovarian cancer, especially in patients with suggestive personal or family histories.

Autosomal dominant inheritance of MSH6 variants underlies Lynch syndrome–associated ovarian cancer. Pathogenic truncating and splice-site mutations in MSH6 have been documented in unselected and high-risk ovarian cancer cohorts, with protein loss confirmed by immunohistochemistry and microsatellite instability (MSI) testing. MSI-high status and absent MSH6 staining in tumors align with loss-of-function and support causality.

Genetic evidence includes identification of six ovarian cancer probands with MSH6 mutations (1.29%) in a panel study ([PMID:25622547]) and nine pathogenic carriers among 33 tested high-risk women (27%) ([PMID:32917768]). A representative variant is c.3103C>T (p.Arg1035Ter) in ovarian carcinoma ([PMID:22006311]). Co-segregation of MSH6 alleles with early-onset ovarian cancer has been observed in multiple Lynch syndrome families, supporting clinical actionability.

Functional studies demonstrate that MSH6-deficient ovarian tumors exhibit MSI-high phenotypes and loss of MSH6 protein by IHC, consistent across cohorts ([PMID:21388660], [PMID:32917768]). In vitro assays confirm that truncating and splice-site mutations abrogate MSH6 mismatch repair activity, leading to genomic instability.

Integration of genetic and functional data yields a definitive gene-disease association. MSH6 testing in ovarian cancer patients enables identification of Lynch syndrome carriers, informs surveillance for colorectal and endometrial cancers, and guides prophylactic measures. As routine panels now include MSH6, its assessment has direct clinical utility.

Key Take-home: Germline MSH6 variants drive autosomal dominant ovarian cancer predisposition via mismatch repair deficiency; testing is essential for Lynch syndrome diagnosis and tailored risk management.

References

• Proceedings of the National Academy of Sciences • 2011 • Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. PMID:22006311
• British Journal of Cancer • 2012 • Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. PMID:23047549
• Gynecologic Oncology • 2011 • Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. PMID:21388660
• Journal of Medical Genetics • 2021 • Assessment of mismatch repair deficiency in ovarian cancer. PMID:32917768

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