Meta-analysis finds 3.2% prevalence of germline MMR mutations in patients with upper tract urothelial carcinoma

This systematic review and meta-analysis aimed to quantify the prevalence of germline mutations in DNA mismatch repair (MMR) genes among patients diagnosed with upper tract urothelial carcinoma (UTUC). The analysis synthesized data from 14 individual studies, encompassing a total of 2378 patients with UTUC. The specific study designs, settings, and detailed inclusion criteria of the original studies were not reported in the meta-analysis. The population was defined solely as patients with UTUC, with no further demographic or clinical stratification provided in the aggregated results.

As a prevalence study, there was no specific intervention or comparator. The exposure of interest was the presence of a germline mutation in one of the MMR genes (MSH2, MSH6, MLH1, PMS2). The methodology for genetic testing (e.g., sequencing panels, immunohistochemistry screening) and the specific protocols used across the included studies were not detailed in the meta-analysis findings.

The primary outcome was the pooled prevalence of germline MMR mutations. The analysis found that 3.2% of patients with UTUC carried a pathogenic germline MMR mutation, with a 95% confidence interval ranging from 2.1% to 4.4%. This translates to an estimated 1 in approximately 31 UTUC patients having Lynch syndrome based on this genetic definition. The absolute numbers of mutation-positive patients from the constituent studies were not reported.

Several key secondary outcomes were analyzed. First, the prevalence differed by geographic region: 2.4% in studies from East Asia (China/Japan) versus 4.7% in studies from North America and Europe. However, this difference did not reach statistical significance (P=0.087). Second, MSH2 was identified as the most commonly mutated gene among mutation-positive UTUC patients, though specific prevalence rates for each gene were not provided. Third, a notable 86% of patients found to have a germline MMR mutation were either under 60 years of age at diagnosis or had a personal history of a prior cancer diagnosis.

Safety and tolerability data specific to genetic testing or clinical management were not reported in this meta-analysis, as it focused solely on prevalence estimates. The review did not report on adverse events, psychological impacts of testing, or outcomes related to subsequent surveillance.

These results provide important context within the landscape of Lynch syndrome-associated cancers. The pooled prevalence of 3.2% in UTUC is similar to established prevalence rates in colorectal cancer (approximately 2-3%) and endometrial cancer (approximately 2-5%), for which universal or selective screening for Lynch syndrome is already recommended. This similarity strengthens the biological rationale for considering UTUC as a sentinel cancer for Lynch syndrome, aligning it with other hallmark Lynch-associated malignancies.

The meta-analysis authors noted several methodological limitations. There was moderate statistical heterogeneity among the included studies, with an I² value of 54%, indicating that nearly half of the variability in prevalence estimates is due to differences between studies rather than chance. Publication bias was assessed using Egger's test, though the specific result was not reported. A notable limitation is the geographic distribution of the underlying studies: 8 were from China or Japan, with the remainder from the United States or Europe. This distribution may influence the generalizability of the pooled estimate and could partially explain the observed (though non-significant) regional prevalence difference. The analysis is also limited by the aggregated nature of the data, lacking patient-level details on age, tumor staging, family history, or specific testing methodologies that could inform more nuanced risk stratification.

The clinical implication is that the prevalence of Lynch syndrome among patients with UTUC appears substantial and comparable to other cancers with established testing guidelines. This evidence supports a more proactive approach to genetic evaluation in this patient population. Clinicians should consider germline genetic testing for Lynch syndrome in patients diagnosed with UTUC, particularly those under 60 years of age or with a personal history of another cancer, as 86% of mutation carriers in this analysis fell into one of these categories. Integrating UTUC into existing Lynch syndrome diagnostic algorithms could improve detection rates and facilitate cascade testing for at-risk family members.

Several important questions remain unanswered. The optimal diagnostic strategy—whether universal testing for all UTUC patients or a selective approach based on age, personal/family history, or tumor characteristics (like microsatellite instability)—requires prospective validation. The clinical outcomes of mutation-positive UTUC patients, including their response to therapies like immune checkpoint inhibitors and their cancer-specific survival, are not addressed by this prevalence data. Furthermore, the cost-effectiveness of different testing strategies in the UTUC population has not been established. Finally, the reasons behind the observed geographic variation in prevalence warrant further investigation to determine if they reflect true biological differences, disparities in access to genetic testing, or variations in study methodologies.