Pathway analysis of primary human non-small cell lung cancer (NSCLC).

Abstract

10573 Background: We aimed to increase understanding of NSCLC pathogenesis through characterization of molecular and pathway signatures in primary lung adenocarcinoma (ADC) and squamous cell carcinoma (SSC) samples matched with syngeneic uninvolved normal lung tissue. Methods: Microarrary profiling of ADC and SSC matched with pathologically normal lung tissue (n=20 each) was conducted using the Affymetrix Human Gene 1.0 ST array. The differential expression profile of cancer vs syngeneic normal tissue was calculated for each patient and for combined samples using an unpaired t-test. Pathway analyses based on gene expression profiling were performed using Pathway Studio (Ariadne Genomics, Inc). Functional enrichment was performed using Fisher's exact test and Mann–Whitney test. Results: Transcriptional regulators E2F, CTGF and PDGF were implicated in lung cancer pathogenesis. SSC was characterized by involvement of EGF, IL1F8 and CX3CL1 pathways, while changes in RB1, mir-200 and EMP2 targets were specific for ADC. Cell cycle and metastatic processes were significantly affected in ADC and SCC. Cell cycle genes TOP2A, CCNB1, MELK, MAD2L1, SFN, CDC6, ASPM and TOPBP1 were significantly upregulated in SSC, opposed to just TOP2A in ADC. The biochemical signature pinpoints changes in purine and pyrimidine biosynthesis and energy production pathways, which were common in ADC and SSC. DNA repair genes RBBP8, PRKDC, SHFM1, and PCNA were significantly upregulated (2-fold or more; p<0.001) in SCC. All oncogenes in ADC, and most in SCC, were significantly downregulated, including FOS and FOSB. In SSC, the oncogenes ECT2 and DCUN1D1 were upregulated. In SCC, tumor suppressors DLG1 and DLGAP5 were upregulated, and TGFBR2 was downregulated. No significant changes were detected in DNA repair genes in ADC, in apoptotic genes in ADC or SCC, or in tumor suppressor genes in ADC. Pathway signatures of lung ADC and SCC show both similarities and differences to triple-negative breast cancer (TNBC). Significant changes in NAD metabolism appear to be unique to TNBC and ADC. Conclusions: Lung ADC and SCC are characterized by distinct alterations in DNA repair, cell cycle regulation, and metabolism, thus providing a molecular basis for novel therapeutic strategies.