Abstract 4841: Combining array-based approaches for the identification of candidate loci and related molecules in non-small lung cancer (NSCLC)

Abstract

Abstract OBJECTIVE: Chromosomal regions harboring tumor suppressors and oncogenes are often deleted or amplified. These genomic abnormalities in NSCLC have been extensively examined by classical cytogenetics, microarray-based comparative genomic hybridization and single nucleotide polymorphism (SNP) genomic microarrays techniques, pointing out a number of alterations in genomic regions that correlate with the neoplastic phenotype. Although there are significant technical advances, the genetics underlying the genesis and progression of NSCLC remain poorly understood. In addition to identifying novel loci related to survival and other clinicopathological parameters in a well characterized cohort, we have undertaken an integrated genetic approach to discover novel miRNA that are deregulated in NSCLC. EXPERIMENTAL DESIGN: A total of 125 primary NSCLC specimens with matched normal [60 adenocarcinoma (ADC), 53 squamous cell carcinomas (SCC) and 12 other subtypes] were analyzed for genome-wide LOH/copy number changes using SNP hybridization arrays representing ∼11,500 SNPs. Each of the samples of this cohort has at least 10 years of follow-up. Genome-wide LOH and copy number pattern and statistical analysis were performed using the dChip software. To study association between allelic imbalance/LOH and deregulation of miRNAs, we analyzed a subset (8 pairs) of samples for miRNA expression and correlate the miRNA expression profile with allelic imbalance data generated by SNP analysis. Two types of analysis (The average expression ratio for each miRNA and Mean tumor expression profile) were carried out to identify probes which show differential expression between tumor and adjacent normal tissues and the finding were correlated with allelic imbalance area determined by SNP array analysis. RESULTS: In addition to confirm previously reported loci (LOH and copy number changes on 2q, 4q, 5q, 8p, 8q21, 9p22, 19q13), we identified novel LOH on 1q42 and copy number amplification on 1q21.1 and 1q32-q42 region. We have enriched our NSCLC cohort with molecular phenotypic information of key genes known to be involved in NSCLC pathogenesis (e.g., p53, kras, braf, egfr, etc) and new genes identified in amplified area of ADC include CHD1L, S100A10, KCNH1 and RAB6A etc. Furthermore, we identified several over (miR-205, miR-296) or under-expressed (miR-126, miR-23b, miR-145, Let-7b) miRNAs in tumor samples and our initial findings is consistent with the previous concept that majority of miRNA deregulated in the paired samples are positioned in instable area of the genome. CONCLUSION: Novel cancer related genes can be identified using different complementary analysis and different cohort of samples. Integration of genomic analysis and miRNA expression profiling can identify novel miRNA and potential novel pathways involved in NSCLC pathogenesis. 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 4841. doi:10.1158/1538-7445.AM2011-4841