PDF file - 242K, Table S2. Clinical characteristics of patients in the first replication set (UBC). Table S3. Clinical characteristics of patients in the second replication set (Groningen). Figure S1. Volcano plots showing the impact of smoking, COPD, and lung cancer on gene expression in the lung. Figure S2. Comparison of gene expression recovery following smoking cessation between the discovery set (Laval) and UBC. Figure S3. Comparison of gene expression recovery following smoking cessation between the discovery set (Laval) and Groningen. Figure S4. Expression of SERPIND1 in lung parenchyma of smoker and never-smoker by immunochemistry. Figure S5. Enrichment plot for slowly reversible gene in UBC. Figure S6. Enrichment plot for slowly reversible gene in Groningen
ARTICLE ABSTRACT
Cigarette smoking is the leading risk factor for lung cancer. To identify genes deregulated by smoking and to distinguish gene expression changes that are reversible and persistent following smoking cessation, we carried out genome-wide gene expression profiling on nontumor lung tissue from 853 patients with lung cancer. Gene expression levels were compared between never and current smokers, and time-dependent changes in gene expression were studied in former smokers. A total of 3,223 transcripts were differentially expressed between smoking groups in the discovery set (n = 344, P < 1.29 × 10−6). A substantial number of smoking-induced genes also were validated in two replication sets (n = 285 and 224), and a gene expression signature of 599 transcripts consistently segregated never from current smokers across all three sets. The expression of the majority of these genes reverted to never-smoker levels following smoking cessation, although the time course of normalization differed widely among transcripts. Moreover, some genes showed very slow or no reversibility in expression, including SERPIND1, which was found to be the most consistent gene permanently altered by smoking in the three sets. Our findings therefore indicate that smoking deregulates many genes, many of which reverse to normal following smoking cessation. However, a subset of genes remains altered even decades following smoking cessation and may account, at least in part, for the residual risk of lung cancer among former smokers. Cancer Res; 72(15); 3753–63. ©2012 AACR.
