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

Oncogene volume 27, pages 4615–4624 (2008)Cite this article

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.

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Acknowledgements

This work was supported by funds from CIHR, Genome Canada/BC, Lung Cancer SPORE P50CA70907, DOD VITAL, the Gillson Longenbaugh and Anderson Charitable Foundations as well as scholarships from NSERC, CIHR and MSFHR to WWL, RC and BPC.

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Authors and Affiliations

  1. Departments of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada

    W W Lockwood, R Chari, B P Coe & W L Lam

  2. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA

    L Girard, A F Gazdar & J D Minna

  3. Department of Cancer Imaging, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada

    C MacAulay & S Lam

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  1. W W Lockwood
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  2. R Chari
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  3. B P Coe
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  4. L Girard
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  9. W L Lam
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Correspondence to W W Lockwood.

Additional information

Data deposition: Gene Expression Omnibus, accession number GSE-4824.

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lockwood, W., Chari, R., Coe, B. et al. DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene 27, 4615–4624 (2008). https://doi.org/10.1038/onc.2008.98

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