Abstract 2216: The role of cytosine modifications in cellular sensitivity to cytarabine.

Abstract

Abstract Introduction: Inter-individual differences in cytosine modifications are a result of genetic and environmental influences. 5-methylcytosine and 5-hydroxymethylcytosine are covalent cytosine modifications that occur in CpG dinucleotides throughout the human genome. Objective: To characterize inter-individual variation in cytosine modifications in HapMap samples and investigate the contribution this may have on downstream phenotypes, such as cellular sensitivity to chemotherapeutics, such as cytarabine. Model: Cytosine modification levels at >485,000 CpGs were measured in the International HapMap lymphoblastoid cell lines (LCLs). We utilized the Illumina Infinium 450K HumanMethylation Beadchip array to measure cytosine modification levels in 73 unrelated African (YRI - Yoruba people from Ibadan, Nigeria) and 60 European ancestry (CEU - Caucasians from Utah, US) LCLs. In addition, we evaluated LCL sensitivity to cytarabine in these HapMap cell lines. Results: We performed a linear regression model in order to identify novel associations between cytosine modifications and cytarabine-induced cytotoxicity. From these analyses, we found that promoter methylation of CDC6 and CCDC37 was associated with cytarabine IC50 (p= 3.75 x 10−6 and p= 5.39x 10−6, respectively). Furthermore, it has been shown previously that SNPs associated with pharmacological traits in LCLs are enriched in expression quantitative trait loci (eQTLs). We interrogated SNPs associated with cytosine modification (mSNPs) to help us understand the role of mSNPs in pharmacologic trait-associated genetic variants. We found that SNPs associated with cytarabine are enriched in cis-acting mSNPs in LCLs derived from individuals of European descent. Next, we integrated genome-wide cytosine modification data with genotype and gene expression data available for HapMap LCLs to allow for a more comprehensive understanding of inter-individual genetic variation. We identified a SNP in SLFN5 that was significantly associated with cytarabine sensitivity that is a cis-acting eQTL and mSNP for SLFN5 gene expression and cytosine modification. Conclusions: Analyzing cytosine modification-drug phenotype data may identify novel candidate genes associated with sensitivity to cytarabine. In addition, integrating genotype and gene expression data allow for a better understanding of the biological function underlying pharmacologic trait-associated SNPs. Citation Format: Erika L. Moen, Wenbo Mu, Lucy A. Godley, M. Eileen Dolan, Wei Zhang. The role of cytosine modifications in cellular sensitivity to cytarabine. [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 2216. doi:10.1158/1538-7445.AM2013-2216