Universally offered germline testing in upper tract urothelial carcinoma.

PURPOSE: Upper tract urothelial carcinoma (UTUC) is a common extracolonic manifestation of Lynch syndrome (LS) characterized by mismatch repair deficiency (MMR-D) and microsatellite instability (MSI). LS detection in UTUC relies on tissue- and clinical-based screening, which can fail to detect pathogenic germline variants (PGVs). We sought to determine the prevalence and spectrum of PGVs in UTUC through universally offered germline testing.

METHODS

In this retrospective, single-institution cohort, between 2020 and 2025, UTUC patients were universally offered germline testing, at no cost, irrespective of hereditary cancer suspicion. Concordance between germline findings and immunohistochemistry (IHC), MSI status, and screening criteria was assessed.

RESULTS

Of patients referred, 46% (128 of 281) completed testing. LS-associated MMR PGVs were detected in 3.1% (n = 4) and overall PGVs in 6.3% (n = 8). PGVs included MSH6 (n = 3), MSH2 (n = 1), BRCA1 (n = 2), CHEK2 (n = 1), and monoallelic NTHL1 (n = 1). Of MMR PGV carriers, NCCN LS screening criteria identified 50% (2 of 4), Amsterdam II identified none, and 1 patient scored below the PREMM5 ≥ 2.5% threshold. IHC was discordant in 78% (7 of 9) of MMR-D patients who lacked a germline MMR PGV; 50% (2 of 4) of MMR PGV carriers had intact MMR expression. One MSH6 PGV carrier was not detected by any screening strategy.

CONCLUSIONS

LS-associated PGV prevalence in UTUC mirrors colorectal and endometrial cancer cohorts undergoing universal genetic testing, where LS testing is standard, supporting liberalized referral for germline testing.