1. ¹Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
2. ²Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
3. ³Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
4. ⁴Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
5. ⁵Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
6. ⁶Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
7. ⁷Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Correspondence: Dr M Ladanyi, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room S-801, New York, NY 10065, USA. E-mail: ladanyim@mskcc.org

⁸These authors contributed equally to this work.

Deceased.

Received 20 October 2008; Revised 3 April 2009; Accepted 5 April 2009; Published online 15 June 2009.

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.