Abstract 1115: Germline single nucleotide polymorphisms in DNA repair genes in urothelial cancer patients
Authors: Faltas Bishoy M. , Vlachostergios Panagiotis J. , Lam Linda , Zhang Tuo , Elemento Olivier , Rubin Mark A. 
Published: July 2017

Abstract
Introduction: Germline single nucleotide polymorphisms (SNPs) have been investigated in several cancers. Repair of DNA damage is a key cellular process involved in the development of chemotherapy-resistance. The role of germline SNPs in DNA damage repair genes (DRGs) in determining resistance to DNA-damaging agents in urothelial carcinoma (UC) patients is not completely understood.
Methods: We examined a cohort of 53 UC patients (median age 67, 42 males) enrolled in our IRB-approved Precision Medicine program. Patients had histologically confirmed UC (43 bladder, 10 upper tract UC) and received treatment with platinum-based chemotherapy. We isolated germline DNA from peripheral blood lymphocytes or buccal swabs, and used whole exome sequencing (WES) to examine germline SNPs. As a reference for SNP frequencies we used the Exome Aggregation Consortium (ExAC) database, which represents the largest, randomly selected, germline WES database in the general population, including 60,706 individuals, among which 7,601 patients with multiple cancer types from the Tumor Cancer Genome Atlas (TCGA) cohort.
Results: Twelve different DRG SNPs were identified in germline DNA samples from 53 patients, affecting genes involved in non-homologous end-joining (RECQL4, n = 18, 54.50%; POLQ, n = 2, 6%), nucleotide excision repair (ERCC6, n = 2, 6%; XPA, n = 1, 3%; CCNH, n = 1, 3%; POLK, n = 1, 3%), homologous recombination (RNF168, n = 1, 3%; RAD17, n = 1, 3%; POLE, n = 1, 3%), Fanconi anemia pathway (POLN, n = 1, 3%), mismatch repair (EXO1, n = 1, 3%) and mitochondrial DNA repair (POLG, n = 2, 6%). The frequency of rs11342077 of the DNA helicase RECQL4 was significantly higher in our cohort (18/53, 34%) compared to its frequency in the ExAC database (p&lt;0.01%). There was no significant difference in overall survival (OS) between patients with and without DRG SNPs (log-rank p=0.46). There was no significant association between the most commonly identified SNP, rs11342077, and overall survival among UC patients with DRG SNPs (log-rank p=0.39). Overall, the presence of DRG SNPs in our cohort occurred at a significantly higher frequency (33/53, 62.3%) compared to the ExAC database (0.56%, chi-square p&lt;0.01).
Conclusions: Germline SNPs in DNA repair pathway genes are common in UC. Additional study of the role of these SNPs as potential biomarkers of response DNA damaging chemotherapeutic agents, including platinum-based chemotherapy or/and PARP inhibitors is needed in a larger cohort.
Citation Format: Bishoy M. Faltas, Panagiotis J. Vlachostergios, Linda Lam, Tuo Zhang, Olivier Elemento, Mark A. Rubin. Germline single nucleotide polymorphisms in DNA repair genes in urothelial cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1115. doi:10.1158/1538-7445.AM2017-1115