An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors Journal Article
| Authors: | Chitale, D.; Gong, Y.; Taylor, B. S.; Broderick, S.; Brennan, C.; Somwar, R.; Golas, B.; Wang, L.; Motoi, N.; Szoke, J.; Reinersman, J. M.; Major, J.; Sander, C.; Seshan, V. E.; Zakowski, M. F.; Rusch, V.; Pao, W.; Gerald, W.; Ladanyi, M. |
| Article Title: | An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors |
| Abstract: | To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers. © 2009 Macmillan Publishers Limited All rights reserved. |
| Keywords: | controlled study; human tissue; somatic mutation; gene deletion; mutation; cancer patient; adenocarcinoma; cell proliferation; in situ hybridization, fluorescence; cluster analysis; gene expression; gene expression profiling; lung neoplasms; genome-wide association study; rna interference; receptor, epidermal growth factor; cell line, tumor; kaplan-meiers estimate; oncogene; tumor suppressor gene; gene expression regulation, neoplastic; lung adenocarcinoma; gene loss; genomics; cyclin-dependent kinase inhibitor p16; array comparative genomic hybridization; egfr; expression profiling; kras; microarray; chromosome 8p; dusp4 gene; egfr gene; lkb1 gene; negative feedback; oncogene k ras; p16 gene; chromosome aberrations; dual-specificity phosphatases; gene dosage; genes, ras; mitogen-activated protein kinase phosphatases; nucleic acid hybridization |
| Journal Title: | Oncogene |
| Volume: | 28 |
| Issue: | 31 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-08-06 |
| Start Page: | 2773 |
| End Page: | 2783 |
| Language: | English |
| DOI: | 10.1038/onc.2009.135 |
| PUBMED: | 19525976 |
| PROVIDER: | scopus |
| PMCID: | PMC2722688 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 20" - "Export Date: 30 November 2010" - "CODEN: ONCNE" - "Source: Scopus" |
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