Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity

Abstract

BackgroundUsing genome-wide genetic, gene expression, and microRNA expression (miRNA) data, we developed an integrative approach to investigate the genetic and epigenetic basis of chemotherapeutic sensitivity.ResultsThrough a sequential multi-stage framework, we identified genes and miRNAs whose expression correlated with platinum sensitivity, mapped these to genomic loci as quantitative trait loci (QTLs), and evaluated the associations between these QTLs and platinum sensitivity. A permutation analysis showed that top findings from our approach have a much lower false discovery rate compared to those from a traditional GWAS of drug sensitivity. Our approach identified five SNPs associated with 10 miRNAs and the expression level of 15 genes, all of which were associated with carboplatin sensitivity. Of particular interest was one SNP (rs11138019), which was associated with the expression of both miR-30d and the gene ABCD2, which were themselves correlated with both carboplatin and cisplatin drug-specific phenotype in the HapMap samples. Functional study found that knocking down ABCD2 in vitro led to increased apoptosis in ovarian cancer cell line SKOV3 after cisplatin treatment. Over-expression of miR-30d in vitro caused a decrease in ABCD2 expression, suggesting a functional relationship between the two.ConclusionsWe developed an integrative approach to the investigation of the genetic and epigenetic basis of human complex traits. Our approach outperformed standard GWAS and provided hints at potential biological function. The relationships between ABCD2 and miR-30d, and ABCD2 and platin sensitivity were experimentally validated, suggesting a functional role of ABCD2 and miR-30d in sensitivity to platinating agents.

Coordination compounds in cancer: Past, present and perspectives

“…Further integration of global gene expression data, miRNA and SNPs into quantitative trait loci (QTLs) allowed for identification of functional links, e.g. between particular SNPs (rs11138019), expression of miRNA (miR30a), activity of membrane efflux transporters (ABCD2) and cisplatin sensitivity in ovarian cancer (LaCroix et al, 2014). Recent global studies focused on other metal-based cytotoxic drugs, e.g.…”

In Vitro Human Cell Line Models to Predict Clinical Response to Anticancer Drugs

“…Mitra et al reported that another FKBP5 intronic SNP, rs3798346, was significantly associated with event-free survival and overall survival in pediatric acute myeloid leukemia (AML) patients treated with cytarabine [56]. This is one among many examples for which our group and others have used LCLs to characterize biomarkers at both functional and mechanistic levels [10–12,14–16,18,19,21–24]. …”

“…Recently additional information for less common and rare variants has been generated by the 1000 Genome Project using Next-Generation Sequencing [42]. This model has also been extensively characterized at the molecular level, including DNA CNV, DNA methylation, mRNA and miRNA expression, protein expression as well as cytotoxicity data for various anticancer drugs [3–7,12,20–22,24–26,59]. These data have also been used to develop statistical methodology related to the integrated analysis of different omic data to help identify pharmacogenomic biomarkers [6,12].…”

“…This model has also been extensively characterized at the molecular level, including DNA CNV, DNA methylation, mRNA and miRNA expression, protein expression as well as cytotoxicity data for various anticancer drugs [3–7,12,20–22,24–26,59]. These data have also been used to develop statistical methodology related to the integrated analysis of different omic data to help identify pharmacogenomic biomarkers [6,12]. In addition to the analysis of SNP, expression and drug cytotoxicity data, a comprehensive GWAS for CNVs identified drug-related CNVs that were independent of SNP signatures [4] and the analysis of protein expression for 441 human signaling proteins and transcription factors in 68 HapMap YRI LCLs found enrichment of protein quantitative trait loci (pQTLs) for cisplatin and paclitaxel response.…”

Epigenetics of Cisplatin Resistance

“…From the analysis for cisplatin, one 1 SNP associated with the expression of 1 miRNA and 1 gene was found (rs11138019 genotype, miR-30d expression, and ABCD2 expression), and functional characterization of this association was confirmed in the SKOV3 ovarian cancer cell line [80]. They then integrated transcriptional gene expression and miRNA expression with their known single nucleotide polymorphism (SNP) genotypes to identify robust SNP associations with the IC 50 .…”