Abstract 646: Identification of novel epigenetic biomarkers for platinum-based chemotherapy resistance in high grade serous ovarian cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Platinum-based chemotherapy has been standard of care for advanced stage ovarian cancer (OC) patients since the last 3 decades. However, majority of patients relapse within 6 months with drug-resistant disease, which entitle OC among the most lethal gynecological malignancy. Besides ‘’classic’’ clinicopathological features of the primary tumor, no biological parameters have shown clinically predictive and prognostic value for chemoresponse in OC. In the present study, we are focusing on the identification of novel DNA methylation markers in response to platinum-based chemotherapy in high grade serous OC. To accomplish this aim, we performed next generation sequencing on methylation-enriched genomic DNA, isolated from frozen OC patient material from responders (more than 18 months progression free survival) and non-responders (less than 6 months progression free survival) to platinum chemoresponse (n=10 in each group). Subsequent robust biostatistics and comparative expression data analysis revealed a list of significantly differentially methylated genes of which a number were checked by methylation specific PCR (MSP) on a large platinum sensitive and resistance OC cell line panel. Gene ontology analysis showed that these genes are frequently associated with cell-fate determination, lineage commitment, transcriptional factor binding and ions-transporter system. Selected candidate methylation markers are currently being validated by pyrosequencing. Moreover, these selected markers are in-silico validated with publically available methylation and expression databases. Next, selected candidate methylation markers will be validated by quantitative-MSP on an independent OC patient cohort. Ultimately, this study will provide a DNA methylation profile for identifying those patients that may benefit from platinum-based chemotherapy in combination with epigenetic treatment modalities. Citation Format: Tushar Tomar, Nicolette G. Alkema, Tim De Meyer, Wim van Criekinge, Harry G. Klip, Gert Jan Meersma, Ate GJ van der Zee, Steven de Jong, G. Bea A. Wisman. Identification of novel epigenetic biomarkers for platinum-based chemotherapy resistance in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 646. doi:10.1158/1538-7445.AM2013-646