Abstract
Alterations in the gene expression of organs in contact with the environment may signal exposure to toxins. To identify genes in lung tissue whose expression levels are altered by cigarette smoking, we compared the transcriptomes of lung tissue between 118 ever smokers and 58 never smokers. In all cases, the tissue studied was non-involved lung tissue obtained at lobectomy from patients with lung adenocarcinoma. Of the 17,097 genes analyzed, 357 were differentially expressed between ever smokers and never smokers (FDR < 0.05), including 290 genes that were up-regulated and 67 down-regulated in ever smokers. For 85 genes, the absolute value of the fold change was ≥2. The gene with the smallest FDR was MYO1A (FDR = 6.9 × 10−4) while the gene with the largest difference between groups was FGG (fold change = 31.60). Overall, 100 of the genes identified in this study (38.6%) had previously been found to associate with smoking in at least one of four previously reported datasets of non-involved lung tissue. Seven genes (KMO, CD1A, SPINK5, TREM2, CYBB, DNASE2B, FGG) were differentially expressed between ever and never smokers in all five datasets, with concordant higher expression in ever smokers. Smoking-induced up-regulation of six of these genes was also observed in a transcription dataset from lung tissue of non-cancer patients. Among the three most significant gene networks, two are involved in immunity and inflammation and one in cell death. Overall, this study shows that the lung parenchyma transcriptome of smokers has altered gene expression and that these alterations are reproducible in different series of smokers across countries. Moreover, this study identified a seven-gene panel that reflects lung tissue exposure to cigarette smoke.
Highlights
Treatment of cell lines or laboratory animals with toxic chemicals alters their metabolism and induces a gene expression signature that reflects the effects of specific toxins or their mode of action
Among the different lung cancer histotypes, lung adenocarcinoma is mainly observed in never smokers and former smokers[11]
We performed a genome-wide transcriptome analysis on non-involved lung tissue from patients with lung adenocarcinoma, including 118 ever smokers and 58 never smokers, to investigate the differences in transcript levels and identify biochemical pathways altered by cigarette smoking
Summary
Treatment of cell lines or laboratory animals with toxic chemicals alters their metabolism and induces a gene expression signature that reflects the effects of specific toxins or their mode of action. A more recent study[8] identified 599 genes in lung tissue whose expression levels differed between never and current smokers, and while in former smokers these alterations had mostly normalized some genes remained up-regulated even 25 years after smoking cessation. Both these studies were carried out on non-involved lung tissue from patients with lung cancer, one of the most common diseases induced by tobacco smoking[9]. We performed a genome-wide transcriptome analysis on non-involved lung tissue from patients with lung adenocarcinoma, including 118 ever smokers and 58 never smokers, to investigate the differences in transcript levels and identify biochemical pathways altered by cigarette smoking
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