Genomic Profiles in Stage I Primary Non Small Cell Lung Cancer Using Comparative Genomic Hybridization Analysis of cDNA Microarrays

Abstract

To investigate the genomic aberrations that are involved in lung tumorigenesis and therefore may be developed as biomarkers for lung cancer diagnosis, we characterized the genomic copy number changes associated with individual genes in 14 tumors from patients with primary non small cell lung cancer (NSCLC). Six squamous cell carcinomas (SQCAs) and eight adenocarcinomas (ADCAs) were examined by high-resolution comparative genomic hybridization (CGH) analysis of cDNA microarray. The SQCAs and ADCAs shared common frequency distributions of recurrent genomic gains of 63 genes and losses of 72 genes. Cluster analysis using 57 genes defined the genomic differences between these two major histologic types of NSCLC. Genomic aberrations from a set of 18 genes showed distinct difference of primary ADCAs from their paired normal lung tissues. The genomic copy number of four genes was validated by fluorescence in situ hybridization of 32 primary NSCLC tumors, including those used for cDNA microarray CGH analysis; a strong correlation with cDNA microarray CGH data emerged. The identified genomic aberrations may be involved in the initiation and progression of lung tumorigenesis and, most importantly, may be developed as new biomarkers for the early detection and classification of lung cancer.

Identification of putative oncogenes in lung adenocarcinoma by a comprehensive functional genomic approach

“…For example, genomic copy number and protein levels of KCIP-1 were previously found to be amplified and overexpressed in primary lung cancers by cDNA clonebased CGH array analysis (Jiang et al, 2004) and proteomic analysis (Chen et al, 2002), respectively. Our functional genomic approach, which integrates simultaneous CGH, transcript microarrys, proteomic analyses, and siRNA, allows us not only to quickly identify potential oncogenes but also to explore their significance as diagnostic and therapeutic targets in tumor progression -more than could be achieved by any technique alone.…”

“…Now, HER-2 aberrations are used as a predictor of response to therapy, and treatment of HER-2-positive breast cancer with the monoclonal anti-HER-2 antibody trastuzumab has been shown to improve prognosis (Ross and Fletcher, 1999). Emerging evidence of common amplicons in lung adenocarcinomas (Luk et al, 2001;Jiang et al, 2004;Tonon et al, 2005) suggests that additional oncogenes remain to be identified; however, conventional techniques are ineffective in pinpointing such oncogenes. Parallel measurement of DNA copy number and mRNA levels in cDNA microarrays permits changes in copy number to be compared with transcription levels on a gene-by-gene basis to generate lists of candidate genes within the defining amplicons (Hyman et al, 2002;Pollack et al, 2002).…”

A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer

“…The present observations of the genes are consistent with our earlier findings, confirming their potential role as biomarkers for early NSCLC. Of the 3 newly characterized genes, ENO1 is located at chromosome 1p36.23 that is one of the most frequent targets of genomic amplification in lung cancer (8,19,20). Racz et al (21) found that ENO1 was amplified in tumors tissues of early stage of NSCLC, especially SCC.…”

“…Analyzing genomic copy number changes of the genes on sputum by using in situ minichip assay The 15 genes that were identified from our previous work (8,19), whose copy number changes were associated with stage I NSCLC are listed in Table 2. We made probes that specifically covered genomic sequences of the target genes as previously described (7).…”

“…Furthermore, taking advantage of the developments in microarray, and based on the principle of in situ hybridization, we developed an in situ minichip assay that examined genomic copy number changes of multiple genes at once (7). In addition, using high-resolution comparative genomic hybridization microarrays, we identified a set of genetic signatures whose copy number changes were associated with early stage NSCLC (8). We further demonstrated that assessing changes of some genes of the signatures could identify cancer cells not only in the cytologically positive sputum, but also in cytologically negative sputum of NSCLC patients (9).…”