With long-term smoking exposure, the DNA sequence suffers persistent miscoding that triggers epigenetic changes in various vital oncogenes, such as NOTCH1, ATK3, DUSP4, SMAD6, and SMARCA4, in the major enriched pathways (see Fig. 2) and leads to carcinogenesis, indicating that the aryl hydrocarbon receptor signaling pathway probably is implicated in the initiation of smoking-induced cancers. This evidence concerns the gene SMAD6 and cancer.