1. Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer
- Author
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Pietzak, Eugene J, Whiting, Karissa, Srinivasan, Preethi, Bandlamudi, Chaitanya, Khurram, Aliya, Joseph, Vijai, Walasek, Aleksandra, Bochner, Emily, Clinton, Timothy, Almassi, Nima, Truong, Hong, de Jesus Escano, Manuel R, Wiseman, Michal, Mandelker, Diana, Kemel, Yelena, Zhang, Liying, Walsh, Michael F, Cadoo, Karen A, Coleman, Jonathan A, Al-Ahmadie, Hikmat, Rosenberg, Jonathan E, Iyer, Gopakumar V, Solit, David B, Ostrovnaya, Irina, Offit, Kenneth, Robson, Mark E, Stadler, Zsofia K, Berger, Michael F, Bajorin, Dean F, Carlo, Maria, and Bochner, Bernard H
- Subjects
Prevention ,Cancer ,Clinical Trials and Supportive Activities ,Urologic Diseases ,Clinical Research ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adjuvants ,Immunologic ,BCG Vaccine ,Carcinoma ,Transitional Cell ,Germ Cells ,Humans ,Neoplasm Invasiveness ,Urinary Bladder Neoplasms ,Xeroderma Pigmentosum Group D Protein ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeIdentification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.Experimental designGermline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed.ResultsA similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma.ConclusionsOur results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.
- Published
- 2022