PMS2 – Prostate Cancer

PMS2 (HGNC:9122) encodes a DNA mismatch repair (MMR) protein whose germline defects cause Lynch syndrome, an autosomal dominant cancer predisposition. In Lynch syndrome cohorts, prostate cancer has been reported in 11 of 188 male PMS2 mutation carriers, yielding a standardized incidence ratio of 4.87 relative to the general population (PMID:24434690). In a prospective analysis of 106 MMR mutation carriers, nine developed prostate cancer, with tumors showing loss of PMS2 expression in seven of eight cases by immunohistochemistry (PMID:19723918). Another registry‐based study of 198 Lynch families observed 97 prostate cancers in 4,127 men (HR 1.99), suggesting a twofold increased lifetime risk for PMS2 carriers (PMID:23530095).

Somatic PMS2 deficiency has also been documented in sporadic prostate tumors: loss of PMS2 protein occurred in 27 of 220 radical prostatectomy specimens (12.3%), and overall MMR protein loss in 50 cases (22.7%) was associated with higher preoperative PSA levels (PMID:32384491). Functional studies in murine and human cells confirm that PMS2 loss impairs repair of tandem mispairs but have not yet modeled prostate‐specific oncogenesis. Available data thus provide limited genetic and functional evidence linking PMS2 disruption to prostate cancer risk and phenotype. Further large‐scale germline and mechanistic investigations are required to establish clinical utility of PMS2 testing in prostate cancer.

Key Take-home: PMS2 germline mutations and somatic protein loss are observed in prostate cancer but current evidence is limited; systematic studies are needed to clarify its role in risk stratification.

References

• Cancer epidemiology, biomarkers & prevention • 2009 • Germ‐line mutations in mismatch repair genes associated with prostate cancer PMID:19723918
• Medicine • 2020 • Loss of DNA mismatch repair proteins in prostate cancer PMID:32384491
• Genetics in medicine • 2014 • Prostate cancer incidence in males with Lynch syndrome PMID:24434690
• Journal of clinical oncology • 2013 • Elevated risk of prostate cancer among men with Lynch syndrome PMID:23530095

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