DNA methylation signature of smoking in lung cancer is enriched for exposure signatures in newborn and adult blood

K M Bakulski,N Lin,J Dou,S J London,J A Colacino,J A Colacino,J A Colacino

doi:10.1038/s41598-019-40963-2

Abstract

Smoking impacts DNA methylation genome-wide in blood of newborns from maternal smoking during pregnancy and adults from personal smoking. We compared smoking-related DNA methylation in lung adenocarcinoma (61 never smokers, 91 current smokers, and 238 former smokers) quantified with the Illumina450k BeadArray in The Cancer Genome Atlas with published large consortium meta-analyses of newborn and adult blood. We assessed whether CpG sites related to smoking in blood from newborns and adults were enriched in the lung adenocarcinoma methylation signal. Testing CpGs differentially methylated by smoke exposure, we identified 296 in lung adenocarcinoma meeting a P < 10−4 cutoff, while previous meta-analyses identified 3,042 in newborn blood, and 8,898 in adult blood meeting the same P < 10−4 cutoff. Lung signals were highly enriched for those seen in newborn (24 overlapping CpGs, Penrichment = 1.2 × 10−18) and adult blood (66 overlapping CpGs, Penrichment = 1.2 × 10−48). The 105 genes annotated to CpGs differentially methylated in lung tumors, but not blood, were enriched for RNA processing ontologies. Some epigenetic alterations associated with cigarette smoke exposure are tissue specific, but others are common across tissues. These findings support the value of blood-based methylation biomarkers for assessing exposure effects in target tissues.

Highlights

One quarter of cancer deaths are attributable to tobacco use[1]
The newborn blood findings were produced by the Pregnancy and Child Epigenetics (PACE) consortium and the adult blood findings were generated by the CHARGE consortium where written informed consent was obtained for all participants and ethical approvals were obtained by the participating studies
DNA methylation data were available on lung adenocarcinomas from 423 individuals in the The Cancer Genome Atlas (TCGA)

Summary

Introduction

One quarter of cancer deaths are attributable to tobacco use[1]. The lung is the primary tissue affected by tobacco smoke and tobacco accounts for 87% of deaths due to lung cancer[1]. We further tested for enriched ontologies from genes annotated to smoking-associated CpG sites that overlapped between lung adenocarcinoma and either newborn or adult blood. Comparing genes mapped to FDR significant smoking-related CpG sites and genes implicated in lung cancer risk from published SNP findings in genome-wide association studies compiled in the GWAS Catalog, two genes overlapped: MYO1G and C6orf[48].

Results

Conclusion