Establishment of a Strong Link Between Smoking and Cancer Pathogenesis through DNA Methylation Analysis

Smoking is a well-documented risk factor in various cancers, especially lung cancer. In the current study, we tested the hypothesis that abnormal DNAm loci associated with smoking are enriched in genes and pathways that convey a risk of cancer by determining whether smoking-related methylated genes led to enrichment in cancer-related pathways. We analyzed two sets of smoking-related methylated genes from 28 studies originating from blood and buccal samples. By analyzing 320 methylated genes from 26 studies on blood samples (N = 17,675), we found 57 enriched pathways associated with different types of cancer (FDR < 0.05). Of these, 11 were also significantly overrepresented in the 661 methylated genes from two studies of buccal samples (N = 1,002). We further found the aryl hydrocarbon receptor signaling pathway plays an important role in the initiation of smoking-attributable cancer. Finally, we constructed a subnetwork of genes important for smoking-attributable cancer from the 48 non-redundant genes in the 11 oncogenic pathways. Of these, genes such as DUSP4 and AKT3 are well documented as being involved in smoking-related lung cancer. In summary, our findings provide robust and systematic evidence in support of smoking's impact on the epigenome, which may be an important contributor to cancer.