Dataset Information

From tobacco smoking to cancer mutational signature: a mediation analysis strategy to explore the role of epigenetic changes.

ABSTRACT:

Background

Tobacco smoking is associated with a unique mutational signature in the human cancer genome. It is unclear whether tobacco smoking-altered DNA methylations and gene expressions affect smoking-related mutational signature.

Methods

We systematically analyzed the smoking-related DNA methylation sites reported from five previous casecontrol studies in peripheral blood cells to identify possible target genes. Using the mediation analysis approach, we evaluated whether the association of tobacco smoking with mutational signature is mediated through altered DNA methylation and expression of these target genes in lung adenocarcinoma tumor tissues.

Results

Based on data obtained from 21,108 blood samples, we identified 374 smoking-related DNA methylation sites, annotated to 248 target genes. Using data from DNA methylations, gene expressions and smoking-related mutational signature generated from ~?7700 tumor tissue samples across 26 cancer types from The Cancer Genome Atlas (TCGA), we found 11 of the 248 target genes whose expressions were associated with smoking-related mutational signature at a Bonferroni-correction P ConclusionsOur findings provide novel insight into the contributions of tobacco smoking to carcinogenesis through the underlying mechanisms of the elevated mutational signature by altered DNA methylations and gene expressions.

SUBMITTER: Chen Z

PROVIDER: S-EPMC7488848 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

From tobacco smoking to cancer mutational signature: a mediation analysis strategy to explore the role of epigenetic changes.

Chen Zhishan Z Wen Wanqing W Cai Qiuyin Q Long Jirong J Wang Ying Y Lin Weiqiang W Shu Xiao-Ou XO Zheng Wei W Guo Xingyi X

BMC cancer 20200914 1

<h4>Background</h4>Tobacco smoking is associated with a unique mutational signature in the human cancer genome. It is unclear whether tobacco smoking-altered DNA methylations and gene expressions affect smoking-related mutational signature.<h4>Methods</h4>We systematically analyzed the smoking-related DNA methylation sites reported from five previous casecontrol studies in peripheral blood cells to identify possible target genes. Using the mediation analysis approach, we evaluated whether the as ...[more]

PMID: 32928150

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Project description:Epigenetics encapsulates a group of molecular mechanisms including DNA methylation, histone modification and microRNAs (miRNAs). Gestational diabetes (GDM) increases the risk of adverse perinatal outcomes and is associated with future offspring risk of obesity and type 2 diabetes. It has been hypothesised that epigenetic mechanisms mediate an effect of GDM on offspring adiposity and type 2 diabetes and this could provide a modifiable mechanism to reduce type 2 diabetes in the next generation. Evidence for this hypothesis is lacking. Epigenetic epidemiology could also contribute to reducing type 2 diabetes by identifying biomarkers that accurately predict risk of GDM and its associated future adverse outcomes. We reviewed published human studies that explored associations between any of maternal GDM, type 2 diabetes, gestational fasting or post-load glucose and any epigenetic marker (DNA methylation, histone modification or miRNA). Of the 81 relevant studies we identified, most focused on the potential role of epigenetic mechanisms in mediating intrauterine effects of GDM on offspring outcomes. Studies were small (median total number of participants 58; median number of GDM cases 27) and most did not attempt replication. The most common epigenetic measure analysed was DNA methylation. Most studies that aimed to explore epigenetic mediation examined associations of in utero exposure to GDM with offspring cord or infant blood/placenta DNA methylation. Exploration of any causal effect, or effect on downstream offspring outcomes, was lacking. There is a need for more robust methods to explore the role of epigenetic mechanisms as possible mediators of effects of exposure to GDM on future risk of obesity and type 2 diabetes. Research to identify epigenetic biomarkers to improve identification of women at risk of GDM and its associated adverse (maternal and offspring) outcomes is currently rare but could contribute to future tools for accurate risk stratification.

Project description:Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.

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Dataset Information

From tobacco smoking to cancer mutational signature: a mediation analysis strategy to explore the role of epigenetic changes.

Background

Methods

Results

Publications

From tobacco smoking to cancer mutational signature: a mediation analysis strategy to explore the role of epigenetic changes.

Similar Datasets

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