Amplification of chromosomal segment 4q12 in non-small cell lung cancer.

Abstract

In cancer, proto-oncogenes are often altered by genomic amplification. Here we report recurrent focal amplifications of chromosomal segment 4q12 overlapping the proto-oncogenes PDGFRA and KIT in non-small cell lung cancer (NSCLC). Single nucleotide polymorphism (SNP) array and fluorescent in situ hybridization (FISH) analysis indicate that 4q12 is amplified in 3-7% of lung adenocarcinomas and 8-10% of lung squamous cell carcinomas. In addition, we demonstrate that the NSCLC cell line NCI-H1703 exhibits focal amplification of PDGFRA and is dependent on PDGFRalpha activity for cell growth. Treatment of NCI-H1703 cells with PDGFRA-specific shRNAs or with the PDGFRalpha/KIT small molecule inhibitors imatinib or sunitinib leads to cell growth inhibition. However, these observations do not extend to NSCLC cell lines with lower-amplitude and broader gains of chromosome 4q. Together these observations implicate PDGFRA and KIT as potential oncogenes in NSCLC, but further study is needed to define the specific characteristics of those tumors that could respond to PDGFRalpha/KIT inhibitors.

• Authors: Alex H Ramos, Amit Dutt, Craig Mermel, Sven Perner, Jeonghee Cho, Christopher J Lafargue, Laura A Johnson, Ann-Cathrin Stiedl, Kumiko E Tanaka, Adam J Bass, Jordi Barretina, Barbara A Weir, Rameen Beroukhim, Roman K Thomas, John D Minna, Lucian R Chirieac, Neal I Lindeman, Thomas Giordano, David G Beer, Patrick Wagner, Ignacio I Wistuba, Mark A Rubin, Matthew Meyerson
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 8 Issue 21 Pg. 2042-50 (Nov 2009) ISSN: 1555-8576 [Electronic] United States
• PMID: 19755855 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Cell Line, Tumor
• Chromosomes, Human, Pair 4
• Gene Amplification
• Gene Dosage
• Humans
• In Situ Hybridization, Fluorescence
• Lung Neoplasms (genetics, pathology)
• Polymorphism, Single Nucleotide
• Proto-Oncogene Proteins c-kit (genetics)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)