Login to Access Video or Poster Abstract: MP48-18
Sources of Funding: Weill Cornell Medical College

Introduction

Single nucleotide polymorphisms (SNPs) in genes involved in carcinogenesis and cancer growth have been investigated for their prognostic value in several cancers, including urothelial (UC). Repair of DNA damage is a key process involved in development of chemotherapy-resistance. The role of germline DNA repair gene (DRG) SNPs in patients with UC has not been explored. We hypothesized that germline SNPs of DRGs could be enriched and potentially associated with outcomes in UC patients exposed to platinum agents.

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 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, the largest randomly selected germline WES database in general population, also including cancer patients.

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<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 OS among UC patients with DRG SNPs (log-rank p=0.39). Overall, the presence of DRG SNPs in our cohort (33/53, 62.3%) occurred at a significantly higher frequency compared to the ExAC database (0.56%, Chi-square p<0.01).

Conclusions

Germline DRG SNPs are more common in UC compared to other cancers, and could play a role as potential biomarkers of response to UC treatment with DNA damaging agents. In addition, if confirmed in larger scale studies, heritable DRG SNPs could potentially be used for identifying patients who will achieve downstaging or complete pathologic response in the neoadjuvant setting.

Funding

Weill Cornell Medical College