Cancer Susceptibility Mutations in Patients With Urothelial Malignancies

Abstract

PURPOSE Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [ P = .004] and 4.6 [ P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The 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. Family history–based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

“…6 Certain genetic syndromes, most notably Lynch syndrome, may also predispose an individual to urothelial carcinoma. 7 The clinical spectrum of bladder cancer can be divided into 3 categories that differ in prognosis, management, and therapeutic aims. The first category consists of non-muscle-invasive disease, for which treatment is directed at reducing recurrences and preventing progression to a more advanced stage.…”

The Prospective Lynch Syndrome Database reports enable evidence-based personal precision health care

“…Ureter and urinary bladder cancers are frequent especially in path_MSH2 carriers, and male path_MSH2 carriers have an additional approximately 25% lifetime risk for prostate cancer. Emerging evidence indicates that carriers of pathogenic variants of many other DNAdamage repair genes are also at risk for urothelial cancers [31].…”

“…If considering families with clinically dominantly inherited MSI tumours as LS, not all families have demonstrable pathogenic MMR variants [32]. Variants in additional DNA repair genes cause urothelial cancer [31]. Also, it is increasingly evident that different classes of variants in the MMR genes are associated with different penetrance the emerging evidence for variants associated with differential splicing being one example [33] and which may be more frequent than is currently recognized [34].…”

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

“…Although it arises from the same urothelium and shares similarities to urothelial carcinoma of the bladder (UCB), UTUC has distinct molecular characteristics that are of clinical significance. Unlike UCB, UTUC is a Lynch Syndrome-associated malignancy, with the most recent study demonstrating 8.7% of UTUC patients having a pathogenic germline mutation in a Lynch Syndrome-associated gene 1 . Given the relative rarity of this cancer type, treatment guidelines such as the recommendation for the use of neoadjuvant chemotherapy are often extrapolated from UCB studies.…”