Alterations in Cell Cycle Genes in Early Stage Lung Adenocarcinoma Identified by Expression Profiling

Abstract

In normal lung epithelial cells, cellular division is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. In contrast, neoplastic lung cells develop the ability to bypass several of these checkpoints, particularly at the G1/S and G2/M boundaries. We used genomic profiling to compare gene expression levels in early stage lung adenocarcinomas and non-neoplastic pulmonary tissue in order to comprehensively identify alterations in the process of cell cycling. RNA extracted from node negative, poorly differentiated lung adenocarcinomas (15 patients) and non-neoplastic pulmonary tissue (5 patients) was hybridized to oligonucleotide microarray filters containing 44,363 genes. Ontological classification was used to extract genes involved with cell cycle progression. Further analysis discovered a subset of differentially expressed genes for further study. Of the 624 cell cycle genes on the microarray filters, 40 genes were predicted to be differentially expressed in lung adenocarcinomas. Alterations in several genes (ie. cyclin B1, cyclin D1, p21, MDM2) are consistent with published data in the literature. We also identified 19 novel genes that have neither been described in non-small cell lung cancer (ie. cdc2, cullin 4A, ZAC, p57, DP-1, GADD45, PISSLRE, cdc20) nor in any other tumors (ie. cyclin F, cullin 5, p34). These results identified several potential cell cycle genes altered in lung cancer.