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MLH1 and Prostate Cancer

Multiple case–control studies have identified single-nucleotide variants in MLH1 associated with overall prostate cancer risk (OR 1.21–1.49) and disease aggressiveness in Caucasian men (rs9852810; [PMID:20056646]). Familial aggregation in Lynch syndrome pedigrees further supports MLH1’s role: 28 prostate cancers occurred in 16 MLH1 mutation carriers and 12 first-degree relatives, with high‐grade tumors in mutation carriers ([PMID:27013479]). Immunohistochemical analyses demonstrated MLH1 protein loss in 69% of prostate tumors from MLH1 carriers, and MSI-high phenotypes were observed in a subset, confirming mismatch repair deficiency in affected tumors ([PMID:25117503], [PMID:27013479]). Recent profiling of primary prostate cancers with MLH1 loss by IHC and long mononucleotide repeat PCR, with biallelic MLH1 deletion in one case, illustrates challenges in standard MSI testing and underscores the utility of IHC/LMR assays to detect MLH1-deficient cancers ([PMID:37196219]). Foundational functional studies in hereditary non-polyposis colon cancer kindreds established MLH1 germline mutations causing truncation or exon skipping and defective repair in lymphoblastoid cells, demonstrating mechanistic plausibility ([PMID:8880570]).

Autosomal dominant inheritance of MLH1 pathogenic variants leads to prostate cancer susceptibility through haploinsufficiency of mismatch repair. Annual screening in mutation carriers enables early detection, and MLH1 testing informs risk stratification and targeted surveillance.

References

  • Cancer epidemiology, biomarkers & prevention • 2010 • Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes. PMID:20056646
  • BMC urology • 2016 • Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. PMID:27013479
  • Journal of clinical oncology • 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
  • JCO precision oncology • 2023 • MLH1 Loss in Primary Prostate Cancer. PMID:37196219
  • Journal of medical genetics • 1996 • Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome. PMID:8880570

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Multiple case–control and population studies with >1,400 cases ([PMID:20056646]), segregation of 28 prostate cancers in Lynch syndrome families ([PMID:27013479]), and concordant functional data.

Genetic Evidence

Strong

MLH1 variants observed in >28 mutation carriers with prostate cancer across unrelated families and co-segregation in first-degree relatives ([PMID:27013479]).

Functional Evidence

Moderate

Demonstrated MLH1 protein loss and MSI in prostate tumors by IHC and PCR ([PMID:25117503], [PMID:37196219]) and defective repair in MLH1-mutant lymphoblastoid cells ([PMID:8880570]).