medwireNews: Clinically significant pathogenic/likely pathogenic (P/LP) germline variants, particularly in DNA damage repair (DDR) genes, are common in patients with advanced urothelial cancer (UC) according to sequencing data.
Maria Carlo (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues calculated the prevalence of P/LP germline variants in 77 cancer-associated genes in 586 patients with UC who underwent tumor germline profiling. They identified 86 variants in 80 (13.7%) patients, with 11 individuals having two P/LP variants each.
High- or moderate-penetrance variants were found in 57 (9.5%) patients, and the most commonly mutated of these genes were BRCA2 (1.5% of patients), MSH2 (1.4%), BRCA1 (1.4%), CHEK2 (1.0%), ERCC3 (0.7%), NBN (0.5%), and RAD50 (0.5%).
Overall, 66 (83%) participants had germline P/LP variants in genes associated with DDR and allele frequency comparisons for the most commonly mutated genes showed patients with UC were a significant 3.68 times and 4.58 times more likely to have mutations in BRCA2 and MSH2 than individuals without cancer.
The researchers note that the activity of some cancer therapies is enhanced by DNA repair defects and therefore “[t]he presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies.”
Indeed, the researchers found that significantly more patients with P/LP variants developed UC at the age of 45 years or younger, at 22% versus 6% of those without the variants.
Yet, 26.3% of patients with high-penetrance P/LP variants and 87.5% of those with moderate-penetrance variants would not have been referred for germline testing according to the current guidelines, Carlo and team report.
“Identification of germline mutations in these patients may allow for enhanced screening and early detection of hereditary cancers in those families for whom testing would not have been undertaken,” they say.
The researchers conclude in the Journal of Clinical Oncology: “Broader germline testing in UC, particularly in those of young ages, should be considered.”
By Catherine Booth
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