Incidence of Germline Genetic Variants in Patients with a Urinary Tract Cancer and Association with Outcomes.

Pathogenic germline variants in DNA repair genes, including mismatch repair genes underlying Lynch syndrome and non-Lynch DDR genes (CHEK2, BRCA1, BRCA2, ATM).

The authors retrospectively assessed pathogenic or likely pathogenic germline variants in 78 cancer predisposition genes among 273 patients with urinary tract cancer (bladder, renal pelvis, ureter, urethra), then validated the frequency in an independent cohort of 5972 patients. In these unselected cohorts, 9.3-9.5% of patients harboured a variant in a predisposition gene, and no clinicodemographic variable predicted its presence. Lynch syndrome was identified in 0.7-0.8% of patients, more often with upper tract disease and strong personal and family cancer histories, whereas non-Lynch DDR variants occurred in 6.6-8.0%, most often in CHEK2, BRCA1, BRCA2 and ATM. In very small subgroups, patients with Lynch syndrome responded well to immune checkpoint inhibitors and those with a DDR variant to platinum-based chemotherapy. The authors conclude that more than one third of carriers are missed by current testing criteria and note that standard variant calling methods may miss large deletions.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The point that matters for practice is the absence of any clinical predictor: if no clinicodemographic criterion flags carriers, then selection on family history as currently practised misses a substantial fraction of patients, the classic argument for broader access to germline testing in urology. Two qualifications: most variants found are moderate-penetrance DDR genes, led by CHEK2, whose causal role in urothelial cancer is not established by frequency alone, and the platinum or checkpoint inhibitor response signals rest on numbers far too small to be more than a hypothesis. The comment on large deletions missed by standard pipelines is a useful laboratory-side reminder, where CNV analysis often remains the poor relation of interpretation.

Analysis by Dr Thibaut Benquey