Abstract 3674: Gene expression analysis of field of cancerization in early stage NSCLC patients towards development of biomarkers for personalized prevention
Authors: Kadara Humam , Saintigny Pierre , Fan Youhong , Chow Chi-Wan , Chu ZuoMing , Lang Wenhua , Behrens Carmen , Gold Kathryn , Liu Diane , Lee J. Jack , Mao Li , Kim Edward S. , Hong Waun K. , Wistuba Ignacio I. 
Published: June 2012

Background: The identification of early stage non-small cell lung cancer (ES NSCLC) patients (pts) at higher risk for recurrence or second primary tumor (SPT) development is vital to personalizing prevention and therapy. We sought to decipher spatial and temporal patterns of gene expression in the airway field of ever-smoker ES NSCLC pts to better understand lung cancer pathogenesis and predict recurrence or SPT development.

Methods: Pts on the prospective Vanguard study had definitively treated ES (I/II) NSCLC, were current/former smokers, and had bronchoscopies with brushings obtained from the main carina (MC) at baseline, 12, and 24 months following resective surgery and from different anatomical regions at baseline. Expression profiling is ongoing for all eligible pts (41 pts, 326 samples). To query temporal and spatial airway expression profiles, two sets of six pts were selected based on complete processed time point and baseline airway site (3 different sites per pt) arrays (Affymetrix Human Gene 1.0 ST), respectively. Temporally and spatially differentially expressed genes were independently identified based on a p&lt;0.01 of a univariate t-test with estimation of the false discovery rate (FDR), studied by hierarchical clustering and principal component analysis (PCA), and functionally analyzed using network analysis.

Results: 871 gene features were differentially expressed among MCs of six NSCLC pts at baseline, 12 and 24 months and were shown to separately group the MCs as evident in both cluster and PC analyses. Moreover, pathways analysis of the temporally modulated genes showed that a gene-network mediated by extracellular regulated kinase (ERK1/2) was most significantly elevated (p&lt;0.001) in function between MCs at 24 months versus baseline. 763 and 931 gene features were differentially expressed between MCs and adjacent-to-resected tumors (ADJ) airways and between MC, ADJ and non-adjacent (distant-to-resected tumor) (NON-ADJ) airways, respectively. Moreover, pathways analysis of the spatially modulated genes revealed that gene-networks mediated by nuclear factor-κB (NF-κB) and ERK1/2-mediated were most significantly elevated (p&lt;0.001) in function in ADJ airway samples versus MCs. Furthermore, PCA revealed that while ADJ airway samples grouped separately and closely together, one MC and 3 NON-ADJ airway samples resided closely with ADJ samples, which were then found to originate from 3 pts with evidence of recurrence, SPT or suspicion of recurrence.

Conclusions: Our findings highlight expression signatures and pathways (ERK1/2 and NF-κB) in a “cancerization field” that may drive lung cancer pathogenesis and be associated with recurrence or SPT development in ES NSCLC pts and thus useful for derivation of biomarkers to guide personalized prevention strategies. Supported by DoD grants W81XWH-04-1-0142 and W81XWH-10-1-1007.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3674. doi:10.1158/1538-7445.AM2011-3674