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

BMC Cancer

Xiao-ou Shu¹  Wanqing Wen¹  Zhishan Chen¹  Wei Zheng¹  Qiuyin Cai¹  Jirong Long¹  Xingyi Guo²  Weiqiang Lin³  Ying Wang³ 

[1] Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 37203, Nashville, TN, USA;Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 37203, Nashville, TN, USA;Department of Biomedical Informatics, Vanderbilt University Medical Center, 37203, Nashville, TN, USA;The Kidney Disease Center, the First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China;

关键词: Gene expression;    Methylation;    Tobacco smoking;    Mutational signature;    Mediation analysis;   

DOI  :  10.1186/s12885-020-07368-1

来源: Springer

【 摘 要 】

BackgroundTobacco 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.MethodsWe 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.ResultsBased 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 < 0.001. This included four for head and neck cancer, and seven for lung adenocarcinoma. In lung adenocarcinoma, our results showed that smoking increased the expression of three genes, AHRR, GPR15, and HDGF, and decreased the expression of two genes, CAPN8, and RPS6KA1, which were consequently associated with increased smoking-related mutational signature. Additional evidence showed that the elevated expression of AHRR and GPR15 were associated with smoking-altered hypomethylations at cg14817490 and cg19859270, respectively, in lung adenocarcinoma tumor tissues. Lastly, we showed that decreased expression of RPS6KA1, were associated with poor survival of lung cancer patients.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.

【 授权许可】

CC BY