Identifying a Clinically Actionable Germline Pathogenic Variant in Patients With UTC

A real-world, multicenter cohort of patients with urinary tract cancer (UTC) from Sumati Gupta, MD, and colleagues published in JCO Precision Oncology investigated factors that could alter the likelihood of identifying a clinically actionable germline pathogenic variant (PV).

Researchers investigated the data of patients with UTC with primary disease sites, including the bladder, urethra, and upper tract, who were treated at 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The study’s data set included abstracted clinical data with germline and tumor genomic data. Comparative analyses were also conducted.

In 16 (4.5%) of the 354 participants, clinically actionable germline PVs in cancer predisposition genes were identified. More patients with primary disease sites in the urethra and upper tract reported PVs, featuring a prevalence of 11.0% compared with 3.6% in patients with a primary disease site in the bladder (P=.04).

Dr. Gupta and colleagues reported no major differences between markers of genomic instability— including tumor mutational burden, microsatellite instability (MSI), and loss of heterozygosity; copy number; and chromosomal instability—in those with PVs and those without (P>.05).

Ten (62%) of the identified PVs were found in homologous recombination repair (HRR) genes, 3 (19%) in mismatch repair (MMR) genes, and 3 (19%) in genes connected with other pathways.

“Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV,” investigators wrote. “A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.”