Genetic Susceptibility To Carcinogens

National Institute Of Environmental Health Sciences

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Abstract

Background. Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to environmentally induced disease. The group has developed genotyping assays for the at-risk variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Population studies indicate that for these candidate susceptibility genes, the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), Pi (GSTP1), N-acetyltransferase (NAT1 and NAT2), XRCC1, XPD, P53 pathway, and NRF2 pathway vary significantly between ethnic groups. Some differences in cancer incidence among groups may be due to genetic differences as well as exposure differences. Mission: Our long-term goal is to understanding how genes, the epigenome and the environment interact to influence risk of environmentally induced disease. To this end we are engaged in Environmental Epigenomics. This encompasses: 1) identification of candidate environmental response genes, 2) discovery and functional characterization of genetic, epigenetic and phenotypic variation in these genes, and; 3) the analysis in population studies of environmental disease susceptibility associated with functional polymorphisms, acquired susceptibility factors such as epigenetic changes and environmental exposures; and the interactions between these factors. Eventually we hope these genomic approaches may identify biomarkers of exposure and effect, that will be predictive of future risk, and potentially useful in precision medicine. A current primary focus is to look at methylation levels of CpG sites in the human genome in relationship to exposures. Methylation profiles in blood and other tissues have promise as exposure biomarkers, markers of early pathology or perhaps biomarkers of disease. This information will allow us to more carefully determine the bounds of human variability to guide risk assessment and may be useful in developing prevention strategies to reduce disease incidence. In the Genetic Susceptibility Project we take the candidate susceptibility factors from the laboratory genotype/phenotype studies and test them in population studies. We are collaborating with numerous NIH, and university-based epidemiology groups to design and carryout appropriate tests of these factors in population-based epidemiology studies. Progress/accomplishments: 1) The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53 binding sites could influence cancer. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants and expression quantitative trait loci (eQTLs) in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The p53 pathway cancer-associated polymorphisms have strikingly similar characteristics to well-studied p53 pathway mutations. Our results enable insights into p53-mediated tumor suppression in humans and into p53 pathway-based surveillance and treatment strategies Stracquadanio et al. We not working on p53 in FY18. 2) We are examining CpG methylation in cord blood in relation to maternal smoking and in blood of adult smokers. Epigenetic modifications due to in utero exposures may play a critical role in early programming for childhood and adult illness. 2) We are examining CpG methylation in cord blood in relation to maternal smoking and in blood of adult smokers and relation to disease. Epigenetic modifications due to in utero exposures may play a critical role in early programming for childhood and adult illness. Little is known regarding the epigenetic basis of asthma (Reese et al).Objectives: To identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics (PACE) consortium, we performed epigenome-wide meta-analyses of school-aged asthma and Illumina450K methylation data separately in newborns or older children. We analyzed single CpGs and identified differentially methylated regions (DMRs) using two different methods, namely comb-p and DMRcate. Main Results: In newborns (8 cohorts, 663 cases, 2,902 controls), we identified, at genome-wide statistical significance (FDR<0.05), 9 CpGs differentially methylated in relation to school-aged asthma development. Additionally, 35 regions were differentially methylated using both DMR methods. In the cross-sectional meta-analysis of school-age asthma in relation to methylation in older children (9 cohorts, 657 cases, 2,181 controls) there were 179 CpGs genome-wide significant at FDR<0.05 and 36 differentially methylated regions identified. Pathway analyses highlighted enrichment for asthma-relevant immune processes. Gene expression correlated with methylation at most implicated loci. Functional annotation at all 9 newborn CpGs supports regulatory impact on gene expression. Several implicated genes have druggable targets, including IL5RA and KCNH2. We identified novel loci differentially methylated in newborns for development of asthma by school-age, representing potential biomarkers of asthma risk and numerous novel CpGs and regions in older children related to current asthma that may reflect both risk for and effects of this diseases. These findings may shed light on asthma pathogenesis.