Toxicogenomics and Cancer Susceptibility: Advances with Next-Generation Sequencing

Abstract

The aim of this review is to comprehensively summarize the recent achievements in the field of toxicogenomics and cancer research regarding genetic-environmental interactions in carcinogenesis and detection of genetic aberrations in cancer genomes by next-generation sequencing technology. Cancer is primarily a genetic disease in which genetic factors and environmental stimuli interact to cause genetic and epigenetic aberrations in human cells. Mutations in the germline act as either high-penetrance alleles that strongly increase the risk of cancer development, or as low-penetrance alleles that mildly change an individual's susceptibility to cancer. Somatic mutations, resulting from either DNA damage induced by exposure to environmental mutagens or from spontaneous errors in DNA replication or repair are involved in the development or progression of the cancer. Induced or spontaneous changes in the epigenome may also drive carcinogenesis. Advances in next-generation sequencing technology provide us opportunities to accurately, economically, and rapidly identify genetic variants, somatic mutations, gene expression profiles, and epigenetic alterations with single-base resolution. Whole genome sequencing, whole exome sequencing, and RNA sequencing of paired cancer and adjacent normal tissue present a comprehensive picture of the cancer genome. These new findings should benefit public health by providing insights in understanding cancer biology, and in improving cancer diagnosis and therapy.

A systematic evaluation of microRNAs in regulating human hepatic CYP2E1

“…In some cases the altered expression of DMEs contributes to disease susceptibility and to variations in drug efficacy and drug safety [23,30]. For a well-known example that is relevant to this study, CYP2E1 catalyzes the bioactivation of acetaminophen (APAP) to produce a reactive metabolite that leads to liver injury [31].…”

“…Over the past two decades a number of pharmacogenetics studies have reported genetic variations within the promoters, coding regions, and 3′-UTRs of DME genes that are associated with significant functional effects on drug metabolism that influence drug safety and efficacy [30,33]. Recently, additional mechanistic insights have been gained from studies into epigenetic mechanisms that are also involved in the regulation of DME gene expression [34,35].…”

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

“…Evidence documented that miRNAs play an important role in the modulation of the production of drug metabolizing enzymes and transporters through multi-directional interactions among environmental stimuli, the expression of miRNA molecules and genetic polymorphisms [26][27][28][29][30][31][32][33]. As miRNA expression has been reported to be affected by drugs and since miRNAs themselves may affect drug metabolism and toxicity, miRNA expression possesses a significant potential for affecting drug efficacy and drug safety.…”

Micrornas as Pharmacogenomic Biomarkers for Drug Efficacy and Drug Safety Assessment

“…Multiple studies have shown that xenobiotics influence the expression of NRs [30,31] and DMETs [32–34]. Similar to mRNA expression, the expression of miRNAs is tightly controlled by transcription factors [35] that are responsive to environmental challenges, including dietary constituents or metabolites derived from the diet, pollutants and other xenobiotics [9,36]. In addition, the expressions of miRNAs, NRs and DMETs are modulated by single nucleotide polymorphisms (SNPs), which lead to great interindividual variability in drug efficacy and safety.…”