Data from A Comparative and Integrative Approach Identifies <i>ATPase Family, AAA Domain Containing 2</i> as a Likely Driver of Cell Proliferation in Lung Adenocarcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> To identify genetic changes that could drive cancer pathogenesis in never and ever smokers with lung adenocarcinoma.</p><p><b>Experimental Design:</b> We analyzed the copy number and gene expression profiles of lung adenocarcinomas in 165 patients and related the alterations to smoking status. Having found differences in the tumor profiles, we integrated copy number and gene expression data from 80 paired samples.</p><p><b>Results:</b> Amplifications at 8q24.12 overlapping <i>MYC</i> and <i>ATAD2</i> were more frequent in ever smokers. Unsupervised analysis of gene expression revealed two groups: in the group with mainly never smokers, the tumors expressed genes common to normal lung; in the group with more ever smokers, the tumors expressed “proliferative” and “invasive” gene clusters. Integration of copy number and gene expression data identified one module enriched in mitotic genes and MYC targets. Its main associated modulator was <i>ATAD2</i>, a cofactor of <i>MYC</i>. A strong dose–response relationship between <i>ATAD2</i> and proliferation-related gene expression was noted in both never and ever smokers, which was verified in two independent cohorts. Both <i>ATAD2</i> and <i>MYC</i> expression correlated with 8q24.12 amplification and were higher in ever smokers. However, only <i>ATAD2</i>, and not <i>MYC</i>, overexpression explained the behavior of proliferation-related genes and predicted a worse prognosis independently of disease stage in a large validation cohort.</p><p><b>Conclusions:</b> The likely driving force behind <i>MYC</i> contribution to uncontrolled cell proliferation in lung adenocarcinoma is <i>ATAD2</i>. Deregulation of <i>ATAD2</i> is mainly related to gene amplification and is more frequent in ever smokers. <i>Clin Cancer Res; 18(20); 5606–16. ©2012 AACR</i>.</p></div>