PD12-09 INHERITED CANCER PREDISPOSITION GENE VARIANTS IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

Abstract

INTRODUCTION AND OBJECTIVE: Emerging data have shown that patients with locally advanced and metastatic urothelial cancer frequently harbor rare germline variants in cancer predisposition genes, particularly in DNA damage response (DDR) genes. The prevalence of such rare germline variants in patients with non-muscle invasive bladder cancer (NMIBC), the most common form of urothelial cancer, has not been thoroughly studied. METHODS: Patients with NMIBC who were unselected for inherited cancer syndromes were prospectively enrolled in a protocol for molecular profiling of tumor-normal DNA pairs using next-generation sequencing within a CLIA-certified lab (NCT01775072). Germline variation analysis was performed on a clinically annotated cohort of 100 patients with NMIBC that we had previously reported on their somatic mutational spectrum (Pietzak et al Eur Urol 2017). Pathogenic or likely pathogenic (P/LP) germline variants in a panel of 82 genes associated with hereditary cancer predisposition were assessed in accordance with recommendations of the American College of Medical Genetics and Genomics. RESULTS: We identified P/LP germline variants in 12 (15.7%) patients with high-grade NMIBC (n = 76) and 0 patients with low-grade NMIBC (n = 24). Nine (11.8%) patients with high-grade NMIBC had P/LP variants in DDR genes; four were in nucleotide excision repair genes (ERCC2 [2] and ERCC3 [2]) and four were in homologous recombination repair genes (BRCA1 [1], BARD1 [1], RAD50 [1], and RECQL4 [1]). An additional patient had a P/LP germline mutation SDHA and two others had P/LP low-penetrance germline mutations in FH and APC. Interestingly, no patient with a germline mutation had early-onset disease (≤ 45 years at diagnosis) or a family history of urothelial cancer. Compared to patients with high-grade NMIBC without germline variants, those with P/LP germline variants had a higher frequency of nonurothelial cancers (15% vs 42%), Ashkenazi Jewish ancestry (27% vs 42%), and multifocal tumors at initial diagnosis (42% vs 75%). Correlation of P/LP variants with clinical outcomes in a larger cohort is ongoing and is expected to be available for presentation at the meeting. CONCLUSIONS: Our findings suggest that genetic predisposition may play a larger role than expected in NMIBC, as P/LP germline variants were seen in 16% of patients with high-grade NMIBC. If validated, these results may have profound implications for genetic counseling, screening, and prevention. The prevalence of germline DDR variants, which may increase susceptibility to bladder cancer, suggests that therapeutic strategies exploiting tumor vulnerabilities due to impaired DNA repair warrant further investigation in high-grade NMIBC. Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, the National Cancer Institute Cancer Center Core Grant Number P30-CA008748, MSKCC SPORE in Bladder Cancer P50-CA221745, NIH/NCI K12 Paul Calabresi Career Development Award for Clinical Oncology (K12 CA184746)