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Introduction/Background Platinum resistance remains one of the main challenges in the treatment of ovarian high grade serous carcinoma (HGSC). Previous studies demonstrate how genomic alterations alone cannot explain the emergence of acquired platinum resistance. In this scenario, investigating both transcriptome and epigenetic changes appears to be crucial. Methodology Primary cell cultures derived from the ascitic fluid of three chemo-naïve patients with HGSC underwent in vitro pulsed treatment with carboplatin (50uM). Transcriptomic and epigenetic profiles of control and platinum-treated cells were analysed and compared. RNA-sequencing was performed using Illumina NextSeq 2000 and differentially expressed genes (DEGs) identified using DeSeq2 package in R. DNA methylation data were obtained using with Illumina 950K Infinium MethylationEPIC v2.0 BeadChip and analysed using SeSame R package. To assess chromatin accessibility, the assay for transposase accessible chromatin with sequencing (ATAC-Seq) was performed. Results To identify biological mechanisms correlated with persistence following platinum treatment, we focused on the results obtained when combining the three primary cells together. The gene set enrichment analysis (GSEA) of the DEGs showed enrichment in Wnt signalling, MAPK signalling, chromatin remodelling, cell migration and TGF-beta signalling, which suggest the induction of epithelial-mesenchymal transition after treatment. Methylation analysis of platinum-treated cells revealed enrichment in bivalent chromatin state and transcription factors of the Polycomb Repressive Complex, a chromatin regulatory complex involved in maintaining pluripotency in stem cells through the repression of transcription. Analysis of data from ATAC-Seq is still ongoing. Conclusion Transcriptomic and methylation analysis of primary HGSC primary cells treated with pulsed carboplatin revealed a potential role of chromatin remodelling in response to platinum. The acquisition of a stemness phenotype might be a potential driver of acquired resistance. ATACseq results will help to better define the role of epigenetic. Disclosures All authors have declared no conflicts of interest.
Russo et al. (Fri,) studied this question.