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

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, P-enrichment = 1.2 x 10(-18)) and adult blood (66 overlapping CpGs, P-enrichment = 1.2 x 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.