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

W. W. Lockwood, R. Chari, B. P. Coe, L. Girard, C. MacAulay, S. Lam, A. F. Gazdar, J. D. Minna, W. L. Lam

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4615-4624
Number of pages10
JournalOncogene
Volume27
Issue number33
DOIs
StatePublished - Jul 31 2008

Fingerprint

Oncogenes
Lung Neoplasms
Gene Dosage
DNA
Genome
Genes
Neoplasms
Genetic Translocation
Gene Amplification
Gene Frequency
Carcinogenesis
Apoptosis
Cell Line
Growth

Keywords

  • Array CGH
  • EGFR signaling
  • Gene amplification
  • Gene expression
  • Integrative analysis
  • Lung cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lockwood, W. W., Chari, R., Coe, B. P., Girard, L., MacAulay, C., Lam, S., ... Lam, W. L. (2008). DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene, 27(33), 4615-4624. https://doi.org/10.1038/onc.2008.98

DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. / Lockwood, W. W.; Chari, R.; Coe, B. P.; Girard, L.; MacAulay, C.; Lam, S.; Gazdar, A. F.; Minna, J. D.; Lam, W. L.

In: Oncogene, Vol. 27, No. 33, 31.07.2008, p. 4615-4624.

Research output: Contribution to journalArticle

Lockwood, W. W. ; Chari, R. ; Coe, B. P. ; Girard, L. ; MacAulay, C. ; Lam, S. ; Gazdar, A. F. ; Minna, J. D. ; Lam, W. L. / DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. In: Oncogene. 2008 ; Vol. 27, No. 33. pp. 4615-4624.
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