Estimating the prevalence of germline mutations in DNA mismatch repair genes among patients with upper tract urothelial carcinoma: a systematic review and meta-analysis.

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1 and PMS2. The objective of this systematic review was to estimate the prevalence of germline mutations in MMR genes among patients with upper tract urothelial carcinoma (UTUC). Literature searches were performed using MEDLINE, EMBASE and Web of Science Core Collection. Studies of interest were selected and data were abstracted independently by two reviewers. Prevalence estimates were transformed using the Freeman-Tukey method and pooled using a random effects model. Heterogeneity and publication bias were assessed quantitatively using the I2 statistic and Egger's test, respectively. Fourteen studies, which included 2,378 patients, were found. Eight of these studies were performed either in China or Japan, with the remainder coming from the United States and Europe. The pooled prevalence of germline mutations in MMR genes was 3.2% (95% confidence interval [95% CI] 2.1%, 4.4%, I2=54%). The prevalence was lower among studies from East Asia than those from North America and Europe (2.4% vs. 4.7%, P=0.087). MSH2 was the most commonly mutated gene and 86% of the patients who tested positive were less than 60 years of age or had a prior cancer diagnosis. LS prevalence among patients with UTUC is similar to that among patients with colorectal and endometrial cancers, which provides a strong rationale for LS testing in this population. Further research is necessary to determine the optimal diagnostic strategy.