FYI.... *Date:* *Tuesday, June 9, 2015* *Time:* 1:00pm- 2:00pm *Location:* Shady Grove Building – 6W030
*Speaker: *Julia Krushkal *Title: *Expression and exome sequence analysis of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism in the NCI60 cancer cell lines in response to cancer drug treatment *Abstract: *Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation as well as other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth and proliferation. I will describe the use of data and resources from the Transcriptional Pharmacology Workbench to analyze temporal patterns of gene expression changes among epigenetic regulators of DNA methylation and demethylation, and among members of one-carbon pathway in response to treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in regulation of gene expression in multiple pathway components across the NCI60 cell lines, suggesting common underlying biological response mechanisms among different tumors that involve epigenetic response and changes in folate-mediated one-carbon pathway reactions after drug treatment. Information about the timing and direction of response of individual molecular components of these pathways may be helpful in planning the timing and dosage of individual agents in combination therapies. In the second part of my presentation, I will describe an analysis that examined a possible association between DNA sequence variation in exomes of genes involved in DNA methylation, demethylation, and one-carbon metabolism reactions with cell chemosensitivity to drug treatment by individual agents and drug combinations. The results from this sequence analysis remain inconclusive due to a high level of genetic diversity and differences in sensitivity across histological cancer types, suggesting that a much larger number of cell line samples may be needed to conclusively prove a causative effect of association between variants in specific genes and chemosensitivity to treatment.
