Relative Risk of Bladder and Kidney Cancer in Lynch Syndrome: Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Lynch syndrome (LS) is an autosomal dominant hereditary disorder characterised by germline mutation in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletion of the EPCAM gene. LS predisposes affected individuals to an increased lifetime risk of colorectal (30–73%), endometrial (30–51%), genitourinary cancers (2–20%) and various other malignancies. Although LS-associated upper tract urothelial carcinoma cancer has been extensively investigated, evidence surrounding the role of LS in developing bladder and kidney cancer remains scarce and inconclusive. The aim of this study was to quantify the pooled relative risk of bladder and kidney cancer, summarise the existing evidence on screening and provide a useful recommendation to guide clinicians in identifying and diagnosing at risk individuals. ABSTRACT: Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane’s tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as “low” due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.