1. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors
- Author
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Chitale, D, Gong, Y, Taylor, BS, Broderick, S, Brennan, C, Somwar, R, Golas, B, Wang, L, Motoi, N, Szoke, J, Reinersman, JM, Major, J, Sander, C, Seshan, VE, Zakowski, MF, Rusch, V, Pao, W, Gerald, W, and Ladanyi, M
- Subjects
Biotechnology ,Lung Cancer ,Rare Diseases ,Genetics ,Human Genome ,Lung ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Adenocarcinoma ,Cell Line ,Tumor ,Cell Proliferation ,Chromosome Aberrations ,Cluster Analysis ,Cyclin-Dependent Kinase Inhibitor p16 ,Dual-Specificity Phosphatases ,ErbB Receptors ,Female ,Gene Dosage ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Genes ,ras ,Genome-Wide Association Study ,Humans ,In Situ Hybridization ,Fluorescence ,Kaplan-Meier Estimate ,Lung Neoplasms ,Male ,Mitogen-Activated Protein Kinase Phosphatases ,Mutation ,Nucleic Acid Hybridization ,RNA Interference ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - 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.
- Published
- 2009