Abstract 4188: Whole transcriptome analyses of platinum-resistant ovarian cancer cells

Women with advanced stage ovarian cancer have a five-year survival rate of less than 25%. Although most patients respond to platinum-based chemotherapy, relapses are common, leading to platinum-resistant ovarian cancer, which is uniformly fatal. Similar to other malignancies, ovarian cancer progression is associated with transcriptional deregulation and such changes contribute to ovarian cancer progression and development of resistance to chemotherapy. In an effort to better understand the causes of acquired platinum resistance in ovarian cancer, we performed whole transcriptome analysis of platinum sensitive and resistant ovarian cancer cell lines. We used RNA-sequencing to identify candidate genes and pathways that contribute to platinum-resistant ovarian cancer. We detected altered mRNA expression of transcription factors (DMRT3, DMRT1, GATA1, EMX2, LHX1, SRY, SOX9, FOXL2, LHX9) and signaling pathway genes (RXFP2, AR, WT1, FGF9, RSPO1, TUSC3, NROB1, WNT4). Additionally, significant up regulation (>20 fold increase) of the long non-coding RNAs (lncRNAs) HOTAIR and HOTTIP, which direct polycomb group and trithorax complexes to HOX promoters, was detected. We observed elevated HoxA gene expression (> 100 fold in some cases) associated with increased HOTTIP lncRNA expression in the platinum resistant cells. Altered expression of genes associated with DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L MECP2, MBD3L1, MBD6, MBD2, MBD3L2, MBD5, MBD1, MBD3, MBD4) was also observed. Furthermore, the splicing patterns of BRCA1 and BRCA2 genes in platinum resistant cells were altered, resulting in splice variants lacking functional coding regions. Altered BRCA1 and BRCA2 splicing patterns were correlated with reduced expression levels for numerous splicing factors (A2BP1, PTBP1, RBM9, SFRS3, ARID3A, ARID3B, SF1). DNA methylation analysis indicated epigenetic derepression consistent with increased expression for gonad developmental genes (HOTAIR, HOTTIP, HOXA genes). Our data suggest that genes associated ovarian development and differentiation contribute to the development of platinum resistant ovarian cancer. We are currently conducting integrated data and bioinformatics analyses to further investigate changes found in platinum resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4188. doi:1538-7445.AM2012-4188