In our review, we highlight the latest advances in the germline variant landscape of urothelial carcinoma and their potential clinical implications for testing and family screening recommendations. Two large studies were conducted analyzing 586 and 1038 patients with UC derived similar conclusions in terms of the prevalence and distribution of germline pathogenic variants in patients with urothelial carcinoma.4,5 The first study conducted at Memorial Sloan Kettering Cancer Center (MSKCC) included an unselected group of UC patients (n=586 patients), the majority of whom did not have a family history of UC (n=544) or personal history of a second primary (n=474).4 All patients underwent paired tumor and germline testing using MSK-IMPACT. Around 14% of patients harbored at least one pathogenic germline variants. Among those, 66 of 80 patients (83%) were carriers of germline pathogenic or likely pathogenic variants in DDR genes, including BRCA1/2 (2.9%), MSH2 (1.4%), and CHEK2 (1.0%).(4) When these DDR genes' allele frequencies were compared to those from non-cancer subjects in the ExAC database, variants in BRCA2 (odds ratio [OR]= 3.68) and MSH2 (OR= 4.58) were enriched in UC.4 Moreover, pathogenic variant carriers were enriched in patients ≤45 years old. More importantly, approximately a quarter of patients harbored high-penetrance germline variants that would not have been missed by current guidelines that rely largely on family history. This suggests that there may be a potential value for expanding germline testing in UC.
The findings of the first study by the MSKCC group were later supported by our group at the Dana-Farber Cancer Institute (DFCI). We analyzed 1038 patients with UC that were referred to genetic testing at InVitae based on a high suspicion of harboring germline variants.5 Most patients (97%) underwent multigene testing of at least five genes among a total panel of 130 genes. The prevalence of pathogenic germline mutations identified was higher than that in the MSKCC cohort and amounted to 24%, among which DNA-damage repair gene alterations accounted for 19%.5 The figure below shows the average frequency of pathogenic and likely pathogenic variants in each of the DNA-damage repair genes across the two large cohorts.
In the DFCI cohort, almost 19% of patients harbored clinically actionable variants that had clear National Comprehensive Cancer Network management recommendations and exhibited therapeutic or preventive utility. Similar to the work by MSKCC, significant enrichment of pathogenic variants in MSH2 (OR= 15.4), and BRCA2 (OR=5.7) was found in UC patients compared to non-cancer subjects from the ExAC database. Interestingly, pathogenic germline variants in MLH1 (OR= 15.9) and ATM (OR= 3.8) were also enriched in the UC cohort compared to the cancer-free controls from ExAC. Overall, enrichment analysis in the two studies validated known UC-risk genes such as MMR genes and identified two novel cancer-risk genes (ATM and BRCA2). Future adequately controlled enrichment studies are still needed to further validate such findings and to delineate the potential gene-specific UC risk.
With improving technological capabilities and reduced cost of germline genetic testing, more of the unexplored heritability of UC will be elucidated. Until then, the question of performing universal sequencing of heritable cancer-predisposing genes in patients with UC family history- based germline testing remains unanswered. Mounting evidence from these two studies favors the former, as this approach may identify patients that would have otherwise been missed or excluded from current guideline-based testing.
Written by: Amin H. Nassar, MD, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, and Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Guru P. Sonpavde, MD, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
References:
1. Rosenberg, Jonathan E., Peter H. O’Donnell, Arjun V. Balar, Bradley A. McGregor, Elisabeth I. Heath, Evan Y. Yu, Matthew D. Galsky et al. "Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy." Journal of Clinical Oncology 37, no. 29 (2019): 2592.
2. Bellmunt, Joaquim, Ronald De Wit, David J. Vaughn, Yves Fradet, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang et al. "Pembrolizumab as second-line therapy for advanced urothelial carcinoma." New England Journal of Medicine 376, no. 11 (2017): 1015-1026.
3. Powles, Thomas, Ignacio Durán, Michiel S. Van Der Heijden, Yohann Loriot, Nicholas J. Vogelzang, Ugo De Giorgi, Stéphane Oudard et al. "Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial." The Lancet 391, no. 10122 (2018): 748-757.
4. Carlo, Maria I., Vignesh Ravichandran, Preethi Srinavasan, Chaitanya Bandlamudi, Yelena Kemel, Ozge Ceyhan-Birsoy, Semanti Mukherjee et al. "Cancer Susceptibility Mutations in Patients With Urothelial Malignancies." Journal of Clinical Oncology (2019): JCO-19.
5. Nassar, Amin H., Sarah Abou Alaiwi, Saud H. AlDubayan, Nicholas Moore, Kent W. Mouw, David J. Kwiatkowski, Toni K. Choueiri et al. "Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma." Genetics in Medicine (2019): 1-10.
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