DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers

• Published in: Oncogene Vol. 27; no. 33; pp. 4615 - 4624
• Main Authors: Lockwood, W W, Chari, R, Coe, B P, Girard, L, MacAulay, C, Lam, S, Gazdar, A F, Minna, J D, Lam, W L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.07.2008; Nature Publishing; Nature Publishing Group
• Subjects: AKT1 protein; Animals; Apoptosis; Biological and medical sciences; Cancer; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Chromosome translocations; Deoxyribonucleic acid; DNA; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Dosage; Fundamental and applied biological sciences. Psychology; Gene amplification; Gene Amplification - genetics; Gene dosage; Gene Dosage - genetics; Gene expression; Gene frequency; Genetic aspects; Genome, Human; Genomes; Health aspects; Human Genetics; Humans; Internal Medicine; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical sciences; Medicine; Medicine & Public Health; Methods; Molecular and cellular biology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncogenes; Oncogenes - genetics; oncogenomics; Oncology; Physiological aspects; Pneumology; Signal transduction; Signal Transduction - genetics; Translocation, Genetic - genetics; Tumorigenesis; Tumors; Tumors of the respiratory system and mediastinum; Canada; lung cancer; EGFR signaling; integrative analysis; array CGH; gene amplification; gene expression; Lung disease; Respiratory disease; Lung cancer; Activation; Malignant tumor; Gene expression; Carcinogenesis; Mechanism; Gene amplification; DNA; Bronchus disease; Onc gene; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.98

Chromosomal translocation is the best-characterized genetic mechanism for oncogene activation. However, there are documented examples of activation by alternate mechanisms, for example gene dosage increase, though its prevalence is unclear. Here, we answered the fundamental question of the contribution of DNA amplification as a molecular mechanism driving oncogenesis. Comparing 104 cancer lines representing diverse tissue origins identified genes residing in amplification ‘hotspots’ and discovered an unexpected frequency of genes activated by this mechanism. The 3431 amplicons identified represent ∼10 per hematological and ∼36 per epithelial cancer genome. Many recurrently amplified oncogenes were previously known to be activated only by disease-specific translocations. The 135 hotspots identified contain 538 unique genes and are enriched for proliferation, apoptosis and linage-dependency genes, reflecting functions advantageous to tumor growth. Integrating gene dosage with expression data validated the downstream impact of the novel amplification events in both cell lines and clinical samples. For example, multiple downstream components of the EGFR-family-signaling pathway, including CDK5 , AKT1 and SHC1 , are overexpressed as a direct result of gene amplification in lung cancer. Our findings suggest that amplification is far more common a mechanism of oncogene activation than previously believed and that specific regions of the genome are hotspots of amplification.