Abstract
Smoking accounts for almost 80–90% of lung cancer cases, which is also the most frequent cause of cancer-related deaths in humans. With over 60 carcinogens in tobacco smoke, cells dividing at the time of carcinogen exposure are at particular risk of neoplasia. The present study aimed to investigate global gene expression differences in lung adenocarcinoma (LUAD) tumour samples of current smokers and non-smokers, in an attempt to elucidate biological mechanisms underlying divergent smoking effects. Current and non-smoker tumour samples were analysed using bioinformatics tools, examining differences in molecular drivers of cancer initiation and progression, as well as evaluating the effect of smoking and sex on epithelial mesenchymal transition (EMT). As a result, we identified 1150 differentially expressed genes showing visible differences in the expression profiles between the smoking subgroups. The genes were primarily involved in cell cycle, DNA replication, DNA repair, VEGF, GnRH, ErbB and T cell receptor signalling pathways. Our results show that smoking clearly affected E2F transcriptional activity and DNA repair pathways including mismatch repair, base excision repair and homologous recombination. We observed that sex could modify the effects of PLA2G2A and PRG4 in LUAD tumour samples, whereas sex and smoking status might possibly have a biological effect on the EMT-related genes: HEY2, OLFM1, SFRP1 and STRAP. We also identified potential epigenetic changes smoking solely might have on EMT-related genes, which may serve as potential diagnostic and prognostic biomarkers for LUAD patients.
Highlights
Lung cancer represents 12.7% of all new cancer cases and is the most frequent cause of cancer-related deaths worldwide accounting for 18.2% (Ferlay et al 2010)
Subgroups N3 and C3 were eliminated from further analysis, rendering four subgroups best suitable to discriminate lung adenocarcinoma (LUAD) tumour samples according to their smoking status (Supplementary Fig. S4)
Twenty-five genes were identified with a twofold or higher between the smoking subgroups proving some clues on the effect of smoking prevalence on LUAD
Summary
Lung cancer represents 12.7% of all new cancer cases and is the most frequent cause of cancer-related deaths worldwide accounting for 18.2% (Ferlay et al 2010). Tobacco smoke exposure accounts for the majority of lung cancer cases; almost 25% of worldwide cases occur in lifelong never smokers (Lee et al 2011). Never smokers (NS) are defined as individuals who have smoked less than 100 cigarettes during their lifetime (Couraud et al 2015). Carcinogens in cigarette smoke are presumed to induce carcinogenesis in smokers; no such affront exists in NS implying an alternative mechanism. Lung cancer in lifelong never smokers (LCINS) is considered a separate entity with adenocarcinoma predominance (Yano et al 2008), over squamous cell carcinoma (SCC) (Bhopal et al 2019). The UK Million Women Study found three significant risk factors out of 34 potential ones, to be associated with an increased incidence of LCINS and included non-white ethnicity, asthma requiring treatment and tall stature (Pirie et al 2016)
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