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.
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Acknowledgements
We thank Dr Agnes Viale and the MSKCC Genomics Core Laboratory personnel for the generation of microarray data; Dr Laetitia Borsu for assistance with Sequenom assays; Drs Hakim Djaballah and Gabriela E. Sanchez of the MSKCC HTS Core Facility for providing GFP siRNAs; Louis Vargas, Yonghong Xiao and the MSKCC Pathology Core personnel for technical assistance; Drs William Travis, Andre Moreira and David Klimstra for providing pathologic diagnoses; Drs John Minna and Adi Gazdar for providing the human bronchial epithelial cell (HBEC) lines; Drs Alice H Berger, Marasu Niki and Pier Paolo Pandolfi for assistance with reagents and related studies; Dr Roman Thomas for sharing unpublished microarray data, and Dr Harold Varmus for support (to RS). Barry S Taylor is a graduate student in the Department of Physiology and Biophysics, Weill Cornell Graduate School of Medical Sciences. We acknowledge the support of the National Cancer Institute (U01-CA84999 to WG, P01-CA129243 to ML), the Doris Duke Charitable Foundation (to WP), the Long Island League to Abolish Cancer (to WP), the Labrecque Foundation (to WG) and the Lung Cancer Research Foundation (to ML). The MSKCC Sequenom facility is supported by the Anbinder Fund.
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Chitale, D., Gong, Y., Taylor, B. et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 28, 2773–2783 (2009). https://doi.org/10.1038/onc.2009.135
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DOI: https://doi.org/10.1038/onc.2009.135
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