Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival

Abstract

BackgroundTobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.Methodology/Principal FindingsWe performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.Conclusions/SignificanceOur work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.

Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

“…The transcriptome data in the public database (Dyrskjot et al, 2004;Sabates-Bellver et al, 2007;Landi et al, 2008) (Figure 5) strongly support the clinical relevance of our findings. As SKP2 is a promising target of cancer therapy (Frescas and Pagano, 2008;Zhu, 2010), the newly discovered link between RECK and SKP2 may open a new avenue to the therapeutic manipulations of this important pathway.…”

“…Second, among 60 urinary bladder tissues (Dyrskjot et al, 2004), high-RECK/low-SKP2 profiles were found mainly in normal urothelium, normal mucosa and carcinoma in situ, whereas low-RECK/high-SKP2 profiles were found in more malignant tumors: superficial transitional cell carcinoma and muscle invasive carcinoma (Figure 5b). Third, among 108 lung tissues (Landi et al, 2008) (Figure 5c), high-RECK/low-SKP2 profiles were found in normal tissues (right half) and low-RECK/high-SKP2 profiles were found in tumor tissues (left half) with only a few exceptions. These data demonstrate that a direct inverse correlation between the levels of RECK and SKP2 is found in lung, colon and bladder tissues and that a low-RECK/high-SKP2 ratio shows strong association with malignancy in these tissues.…”

Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments

“…We queried Gene Expression Omnibus (GEO) with the keyword “lung” and with the platform set to “GPL570” or “GPL96,” and then selected datasets with a sample size of more than 30. As a result, we got six datasets on platform GPL570, including GSE10245 (n = 40), 34 GSE19188 (n = 110), 35 GSE30219 (n = 83), 36 GSE31210 (n = 224), 37,38 GSE37745 (n = 91), 39 and GSE50081 (n = 128), 40 and five datasets on platform GPL96, including GSE10072 (n = 107), 41 GSE14814 (n = 71), 42 GSE31547 (n = 50), 43 GSE68465 (n = 353), 44 and GSE7670 (n = 54). 45 Detailed information about the datasets is presented in Table 1; the sample numbers are the result of removing patients treated with chemotherapy or radiotherapy.…”

Case series of multiple primary cancers in single individuals: diagnostic and therapeutic dilemmas

“…Multiple primary cancers are an uncommon occurrence and are being recognized more in the literature due to better diagnostic and surveillance techniques [4]. In our first case, smoking was the biggest risk factor leading to synchronous esophageal squamous and lung adenocarcinoma both of which have been associated with smoking [5]. Tobacco and alcohol consumption can lead to high incidence of tongue and oral mucosal cancer [6].…”

“…Lynch syndrome is an inherited disorder with 85% penetrance and the mutations leading to it are mismatch repair genes like hMSH2 , hMLH1 , PMS1 , PMS2 and hMSH6 [7]. It leads to higher incidence of colorectal cancer, endometrial cancer, gastric adenocarcinoma, and ovarian cancers [5]. Familial Adenomatous Polyposis is another inherited disorder with 100% penetrance that happens due to a mutation in the Adenomatous Polyposis Coli ( APC ) gene [8].…”