Abstract 681: Methylation biomarkers of cellular response to demethylating drug

DNA methylation plays an import role in both tumorigenesis and therapy resistance. Demethylating drug regimens have shown efficacy in hematological malignancies, and are actively studied for other cancer types. High variability in patients’ responses to these drugs has been observed and highlights the demand to identify predictive biomarkers for these demethylating drugs. In particular, decitabine (latest FDA-approved demethylating drug) demonstrated as the most potent agent and has the best response on hematological cell lines. Two public datasets were collected to identify methylation biomarkers of decitabine. The first one is from Genomics of Drug Sensitivity in Cancer, with methylation data from Illumina 450K array and drug response from cell lines. The other one is a publicly available patient dataset (methylations from RRBS sequencing and decitabine response from clinic). 64900 CpG sites common to the two methylation platforms were used to train machine learning model (Elastic Net), based on the methylation data and decitabine response (AUC) from 108 hematological cell lines in GDSC. 73 CpGs were identified as predictive biomarkers by Elastic Net. The trained model was then used to make predictions on 39 patients (20 responders and 19 non-responders) with their methylation profiles of the same set of CpGs. The predicted response of responder group is indeed better than non-responder group (p-value = 0.0501), indicating the validity of identified methylation biomarkers. The top one CpG identified by Elastic Net resides in the promoter region of gene C20orf85, and is significantly hypermethylated in non-responder group (p-value = 0.0458), suggesting its potential involvement in the resistance to decitabine. Citation Format: Xuewei Wang, Jean-Pierre Kocher, Zhifu Sun. Methylation biomarkers of cellular response to demethylating drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 681.