Prostate Cancer Risk and DNA Mismatch Repair Deficiency Among Lynch Syndrome Patients.

Background and objective: Lynch syndrome (LS) increases the risk of gastrointestinal, endometrial, and other cancers. Recent data suggest that LS also increases the risk of prostate cancer (PC). Our study aims to characterize the incidence and the clinical and molecular features of PC in LS. Methods: Adult males with LS were identified from an institutional genetic testing registry. PC diagnoses were identified, and tumor tissue was assessed for DNA mismatch repair deficiency (dMMR) by immunohistochemistry. Key findings and limitations: Among 235 adult males with LS, 35 were diagnosed with PC at a median age of 60 yr (interquartile range: 58-69.5). By age 75 yr, the cumulative incidence of any PC and clinically significant PC was 38% (95% confidence interval [CI]: 27-50%) and 26% (95% CI: 16-37%), respectively. MMR deficiency was observed in 75% of tumors from MSH2/EPCAM pathogenic variant (PV) carriers and in 20% from MSH6 PV carriers; no dMMR tumors were observed in MLH1 or PMS2 PV carriers. The majority (71%) of patients with unfavorable intermediate- or higher-risk disease had dMMR tumors, while none with lower-risk disease had dMMR tumors (p < 0.001). LS patients with a family history of PC were three times more likely to develop the disease (26% vs 10%, odds ratio 3.00, p < 0.001) than those without a family history. This study was limited by the number of cases at one institution. Conclusions and clinical implications: MMR-deficient PC was significantly associated with higher-risk clinicopathological features, suggesting that MMR testing should be considered for LS patients with PC to help inform clinical management. Additionally, these data support special consideration of PC screening among LS patients with MSH2, EPCAM, or MSH6 PV, and/or a family history of PC. Patient summary: In this study, we looked at the incidence and characteristics of prostate cancer that develops among individuals with Lynch syndrome. We found that individuals with Lynch syndrome have an elevated risk of developing prostate cancer, but this risk varied by Lynch syndrome gene and family history. This information will help guide targeted prostate cancer screening and management for individuals with Lynch syndrome.