Current smoking‐specific gene expression signature in normal bronchial epithelium is enhanced in squamous cell lung cancer

Boelens, Mirjam C.; Berg, Anke van den; Fehrmann, Rudolf S.N.; Geerlings, Marie; Jong, Wouter K. de; Meerman, Gerard J. te; Sietsma, Hannie; Timens, Wim; Postma, Dirkje S.; Groen, Harry J.M.

doi:10.1002/path.2520

Cited by 61 publications

(54 citation statements)

References 45 publications

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“…Some of the genes that showed enduring alterations in expression have never been reported to be involved in lung cancer, whereas others are targets of Table 3. Replicated probe sets upregulated by smoking and not returning to never-smoker levels within 10 years of smoking cessation in the discovery set and validated in at least one of the 2 replication sets Most whole-genome gene expression studies that have been done to investigate the impact of tobacco smoking were carried out on airways, (6-14) alveolar macrophages, (15)(16)(17) lung tumors, (7,(18)(19)(20)(21), or peripheral leukocytes (22)(23)(24)(25)(26)(27). The impact of tobacco smoking on gene expression in nontumor lung tissue has been evaluated in only a few studies (18,20,21).…”

Section: Discussionmentioning

confidence: 99%

“…Previous transcriptomic studies indicate that a large number of genes are modulated by smoking in airways (6)(7)(8)(9)(10)(11)(12)(13)(14), alveolar macrophages (15)(16)(17), lung tumors (7,(18)(19)(20)(21), and peripheral leukocytes (22)(23)(24)(25)(26)(27). Fewer transcriptomic studies have also examined the effect of the duration of smoking cessation on gene expression profiles (6,8,10,12).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Signature of Smoking in Human Lung Tissues

et al. 2012

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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 ¼ 344, P < 1.29 Â 10 À6 ). A substantial number of smoking-induced genes also were validated in two replication sets (n ¼ 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. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Signature of Smoking in Human Lung Tissues

et al. 2012

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“…1B, discovery cohorts). For each cohort, we trained classifiers based on various feature selection criteria and classifier models, including previously reported smoking-related gene signatures from both normal and tumor tissues (16,(19)(20)(21)39; Supplementary Fig. S2A and S2B and Supplementary Methods).…”

Section: Supervised Classification Of Smoking Status Based On Gene Exmentioning

confidence: 99%

“…Together, this indicates a significant heterogeneity within smoking-defined subgroups of adenocarcinoma. Numerous studies have reported transcriptional differences between never-smokers and smokers in both normal airway epithelium and adenocarcinoma tumor tissue (16)(17)(18)(19)(20)(21)(22)(23). In addition, gene expression-based molecular subgroups in lung adenocarcinoma, e.g., the bronchioid (24) and terminal respiratory unit (TRU; ref.…”

Section: Introductionmentioning

confidence: 99%

Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History

Karlsson

Ringnér

Lauss

et al. 2014

Clinical Cancer Research

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Purpose: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood.Experimental Design: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n ¼ 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups.Results: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies 60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of neversmokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma.Conclusions: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers. Clin Cancer Res; 20(18); 4912-24. Ó2014 AACR.

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“…Studies dating back to 1977 had already made the link and concluded that "lung cancer and COPD share a common familial pathogenetic component associated with pulmonary dysfunction" [2]. More recent studies have confirmed this pathogenetic overlap with the observation that common bronchial epithelial gene expression signatures exist for (ex)-smoking and squamous cell lung cancer [3]. Emerging evidence suggests that progressive lung scarring in the context of idiopathic pulmonary fibrosis (IPF) similarly represents a risk factor for lung carcinogenesis, although causality remains to be definitively established [4], Given that chronic lung diseases such as COPD and IPF occur more frequently in elderly individuals, and that the hallmarks of ageing are closely linked with the hallmarks of cancer development [5], such an overlap is perhaps not entirely surprising.…”

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confidence: 65%