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An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors
Author(s) -
Dhananjay Chitale,
Yongxing Gong,
Barry S. Taylor,
Stephen Broderick,
Cameron Brennan,
Romel Somwar,
Ben Golas,
L Wang,
Noriko Motoi,
János Szőke,
J. Matthew Reinersman,
John E. Major,
Chris Sander,
Venkatraman Seshan,
Maureen F. Zakowski,
Valerie W. Rusch,
William Pao,
William L. Gerald,
Marc Ladanyi
Publication year - 2009
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2009.135
Subject(s) - biology , kras , cdkn2a , cancer research , lung cancer , adenocarcinoma , cancer , mutant , epidermal growth factor receptor , gene , mutation , genetics , oncology , medicine
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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