Abstract 4710: A candidate gene expression signature of early stage lung adenocarcinoma from peripheral whole blood
Authors: Melissa Rotunno, Nan Hu, Chaoyu Wang, Alisa M. Goldstein, Andrew W. Bergen, Dario Consonni, Angela C. Pesatori, Pier Alberto Bertazzi, Sholom Wacholder, Joanna Shih, Neil E. Caporaso, Phil R. Taylor, Maria Teresa Landi
Journal: Cancer Research (2010)

Abstract Background. Early detection in subjects at high risk of lung cancer has great potential to improve survival from this deadly disease. While monitoring the target organ via tissue or imaging is a focus of current screening trials, an accurate blood-based biomarker would be easier and more convenient. No study to date has used blood samples to investigate whole genome expression profiles in lung cancer cases compared to controls. Aims. We identified candidate genetic biomarkers for the detection of early lung adenocarcinoma by contrasting gene expression from peripheral whole blood (PWB) in cases versus controls. Among cases we also explored expression of the identified biomarkers in tumor (T) compared to non involved (NI) lung tissues and their association with survival. Methods. A random sample of 73 stage I adenocarcinoma cases and 80 healthy controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study was studied for genome wide mRNA expression (Affymetrix HG-U133) using PWB collected in PAX tubes (in cases and controls) and from paired snap-frozen T and NI lung tissues (in cases only). A two sample t-test was used to differentiate gene expression in cases compared to controls (overall and stratified by smoking status and by stage), and a linear mixed effects model was used to compare paired T and NI lung tissue samples from cases. Criteria for significance included False Discovery Rate less than or equal to 0.1 and fold changes greater than or equal to 1.5 or less than or equal to 0.66. Cox Proportional Hazards models were used to estimate the effect of gene expression changes on lung cancer survival. Results and Conclusions. We found a gene signature with 20 downregulated and 30 upregulated genes which differentiated stage I cases from controls overall (n=106) and among current smokers (n=39). No significant signature was identified among never (n=30) and former smokers (n=37). Fold changes in stage I cases were consistently stronger than those comparing later stage cases to controls. Downregulation of several T cell receptor and immune related genes in cases compared to controls points to a possibly smoking-related immune impairment at adenocarcinoma initiation. Expression of TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3 genes, all previously implicated in cancer, also differentiated T versus NI lung tissues, suggesting that expression changes of these genes in PWB can be used as markers of related changes in the target organ. In addition, increased ACP1 and TSTA3 expression was associated with adverse survival. Since lung cancer is the most common cause of cancer mortality worldwide and current smokers are at very high risk, our smoking-specific findings, if confirmed and translated into screening approaches, have potential public health impact. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4710.