MSH2 – Breast Cancer Susceptibility

MSH2, a core DNA mismatch repair (MMR) gene, is traditionally implicated in Lynch syndrome but has also been observed in association with breast cancer. Germline heterozygous mutations in MSH2 predispose to MMR deficiency in colorectal and endometrial tumors, and accumulating evidence suggests that breast tumors arising in mutation carriers may similarly exhibit MMR defects and contribute to cancer risk.

Autosomal dominant inheritance of MSH2 mutations has been documented in breast cancer pedigrees. In a Canadian registry of 325 Lynch syndrome–related families, 41 MSH2 mutation carriers from 34 unrelated families developed breast cancer, yielding a lifetime cumulative incidence of 22% and a standardized incidence ratio (SIR) of 3.11 ([PMID:28779004]). A Lebanese pedigree with co-segregation of a splice-site MSH2 variant and early-onset breast cancer further supports segregation of MSH2 mutations with disease phenotype ([PMID:19476642]).

Population-level sequencing corroborates this risk: targeted next-generation sequencing in 711 hereditary breast cancer patients identified 26 (3.6%) carriers of pathogenic MSH2 variants compared with 0.4% in 492 healthy donors (p=0.00013, OR=8.9) ([PMID:32547938]). One recurrent coding change, c.2178G>C (p.Met726Ile), was observed among mutation carriers.

Functional studies demonstrate MMR deficiency in breast tumors from MSH2 mutation carriers. In 107 breast cancers from Lynch syndrome families, 51% of tumors in known MSH2 carriers lacked MSH2 and MSH6 expression by immunohistochemistry and displayed microsatellite instability, mirroring features of colorectal cancers ([PMID:20215533]). This concordance of tumor phenotype with germline status underscores a pathogenic mechanism of MSH2 in breast carcinogenesis.

Conflicting evidence arises from a screening of 59 multiple-case breast cancer families that found no pathogenic MSH2 coding mutations or large rearrangements, suggesting low penetrance or gene-specific effects in some cohorts ([PMID:17922223]).

Integration of family segregation, case-control enrichment, and tumor MMR defects supports a Moderate clinical validity for MSH2 as a breast cancer susceptibility gene. Additional large, prospective studies and functional assays are needed to delineate variant-specific risks and refine screening guidelines.

Key Take-home: Germline MSH2 mutations confer a moderate, autosomal dominant risk for breast cancer and manifest as MMR-deficient tumors, warranting inclusion of MSH2 testing in hereditary breast cancer panels.

References

• Journal of medical genetics • 2017 • Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry PMID:28779004
• Frontiers in oncology • 2020 • Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants PMID:32547938
• Hereditary cancer in clinical practice • 2009 • Early-onset breast cancer in a Lebanese family with Lynch syndrome due to MSH2 gene mutation PMID:19476642
• Familial cancer • 2008 • Is MSH2 a breast cancer susceptibility gene? PMID:17922223
• Clinical cancer research • 2010 • Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry PMID:20215533

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