Abstract 2753: Landscape of somatic mutations in DNA repair genes in prostate cancer

Abstract

Abstract Prostate Cancer (PCa) is a genetic disease that is characterized by multiple genomic alterations. Studies have shown that there is increasing associations between DNA repair genes and PCa. Previously we have reported somatic mutations in Polb and Polk enzymes that are critical for base excision repair and translesion DNA synthesis respectively. In the present study we identified frequently mutated genes that are involved in DNA repair pathway by sequencing all exons of DNA repair pathway genes (129). A total of 57 tumors with matched non tumor tissue was used. Tumors include 24 Caucasians, 21 African Americans (AA). PCa tumors that were ≥6 gleason score and ≥50% of viable tumor cells were only included. All the PCa were procured from Tulane University (TU) Hospital, New Orleans and ethical approvals were obtained from the TU Local Research Ethical Committee. Genomic DNA from tumors was using agilent SureSelect kit was customized to enrich the target that contained all exons of 129 genes of DNA repair pathways. Samples were sent for sequencing by Illumina HiSeq 2000. We validated experimentally somatic mutations in genes that were either affected by somatic non-synonymous or synonymous mutations with a frequency significantly greater than background rates (P<0.05). We considered a somatic mutation to be validated if the targeted sequencing confirmed the presence of the mutation in tumor and it was not found in the matched normal sample. Overall we identified 875 somatic mutations in AA, in which 414 were non-synonymous, 427 synonymous, 14 were stop-gain and 1 was frameshift mutation. AA demonstrated 52 somatic mutations/tumor and Caucasians exhibited 46 somatic mutations/tumor. In terms of Nucleotide excision repair (NER), Mismatch repair (MMR) and Base excision repair (BER) we identified variation in NER, MMR and BER pathways in AA [highest mutation in NER (mean-66) followed by MMR (mean-47) and then BER pathways (mean-37)] whereas our report shows that MMR, BER and NER equally mutated in Caucasians. Furthermore analysis of distribution of mutations between low grade (6) and high-grade Gleason scores (8 or >8) in AA and Caucasians revealed that 12 mutations per tumor for Gleason score 6, versus 22.3 mutations for Gleason 8, 9 or 10. Due to the limitation of samples with gleason score 6 in both races we could not draw a trend individually. Analysis of mutation spectra across the DNA repair genes revealed that C> T transitions (27%) markedly higher in AA PCa followed by T > C transitions (24%). Interestingly in Caucasians PCa C > T transitions (26.8%) were higher including marked increase of C > A (17%) and T > G (17%) transversions. Understanding the mutational changes at the individual patient level could enable personalized treatment and patient selection based on tumor mutational profile for clinical drug testing might be critical for development of new treatments strategies. Support PC094628, and NIH grant 8 P20 GM103518 Citation Format: Santosh Yadav, Muralidharan Anbalagan, Melody Baddoo, Erik Flemington, Krzysztof Moroz, Kathleen Hering-Smith, Nick Makridakis. Landscape of somatic mutations in DNA repair genes in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2753.