Integrative genomic analysis of small-cell lung carcinoma reveals correlates of sensitivity to bcl-2 antagonists and uncovers novel chromosomal gains
| Autor: | Guido Sauter, Stephen K. Tahir, Rick Lesniewski, Edward T. Olejniczak, Gang Wang, Mark G. Anderson, Dimitri Semizarov, Charles Van Sant |
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| Rok vydání: | 2007 |
| Předmět: |
Genetic Markers
Cancer Research Lung Neoplasms Gene Dosage Biology Cell Line Tumor Carcinoma medicine Cluster Analysis Humans Copy-number variation Carcinoma Small Cell Molecular Biology Gene Genotyping Oligonucleotide Array Sequence Analysis Chromosome Aberrations Genome medicine.diagnostic_test Nucleic Acid Hybridization medicine.disease Molecular biology Gene Expression Regulation Neoplastic Real-time polymerase chain reaction Oncology Proto-Oncogene Proteins c-bcl-2 Cancer research Small Cell Lung Carcinoma Chromosomes Human Pair 18 Comparative genomic hybridization Fluorescence in situ hybridization Genes Neoplasm |
| Zdroj: | Molecular cancer research : MCR. 5(4) |
| ISSN: | 1541-7786 |
| Popis: | Cancer is a highly heterogeneous disease in terms of the genetic profile and the response to therapeutics. An early identification of a genomic marker in drug discovery may help select patients that would respond to treatment in clinical trials. Here we suggest coupling compound screening with comparative genomic hybridization analysis of the model systems for early discovery of genomic biomarkers. A Bcl-2 antagonist, ABT-737, has recently been discovered and shown to induce regression of solid tumors, but its activity is limited to a fraction of small-cell lung carcinoma (SCLC) models tested. We used comparative genomic hybridization on high-density single-nucleotide polymorphism genotyping arrays to carry out a genome-wide analysis of 23 SCLC cell lines sensitive and resistant to ABT-737. The screen revealed a number of novel recurrent gene copy number abnormalities, which were also found in an independent data set of 19 SCLC tumors and confirmed by real-time quantitative PCR. A previously unknown amplification was identified on 18q and associated with the sensitivity of SCLC cell lines to ABT-737 and another Bcl-2 antagonist. The region of gain contains Bcl-2 and NOXA, two apoptosis-related genes. Expression microarray profiling showed that the genes residing in the amplified region of 18q are also overexpressed in the sensitive lines relative to the resistant lines. Fluorescence in situ hybridization analysis of tumors revealed that Bcl-2 gain is a frequent event in SCLC. Our findings suggest that 18q21-23 copy number will be a clinically relevant predictor for sensitivity of SCLC to Bcl-2 family inhibitors. The 18q21-23 genomic marker may have a broader application in cancer because Bcl-2 is associated with apoptosis evasion and chemoresistance. (Mol Cancer Res 2007;5(4):331–39) |
| Databáze: | OpenAIRE |
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