Abstract 4326: The chromatin context and consequence of cisplatin-adduct DNA damage

Abstract

Abstract Improvements in survival rates for ovarian cancer lag behind those of other cancers. The combination of paclitaxel and carboplatin, along with debulking surgery, form the primary mode of treatment, however, the majority of patients eventually develop resistance. Epigenetic mechanisms have been implicated in the emergence of drug resistance, with platinum based therapies shown to induce DNA methylation changes at relapse which are associated with overall survival. Using a next generation sequencing approach, including a novel NGS method to map platinum adducts, we sought to investigate the association between platinum-DNA adduct formation and changes to chromatin conformation in the emergence of resistance to platinum therapy. We found chromatin conformation changes at the transcription start sites (TSS) of genes differentially expressed between platinum sensitive and resistant cell lines (p<0.05, n=3 pairs). Furthermore, we found non-TSS associated chromatin conformation changes which distinguish sensitive from resistant lines, and occur primarily in the direction of reduced accessibility in resistant lines (FDR <0.05, log2FC >±1.5). Finally, we found that 2kb windows enriched for platinum-DNA adducts are significantly more accessible than an equal number of random windows on the same chromosome (p<0.05, 1000 permutations). Taken together, these data suggest that platinum treatment may induce epigenetic changes, which reduce chromatin accessibility, rendering cells less susceptible to the formation of platinum-DNA adducts in subsequent treatments, resulting in cells becoming less sensitive to the drug. Citation Format: John Gallon, Erick Loomis, Nicholas Martin, James Flanagan, Robert Brown. The chromatin context and consequence of cisplatin-adduct DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4326.