An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.
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.
Chitale
D
D
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Gong
Y
Y
Taylor
B S
BS
Broderick
S
S
Brennan
C
C
Somwar
R
R
Golas
B
B
Wang
L
L
Motoi
N
N
Szoke
J
J
Reinersman
J M
JM
Major
J
J
Sander
C
C
Seshan
V E
VE
Zakowski
M F
MF
Rusch
V
V
Pao
W
W
Gerald
W
W
Ladanyi
M
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics*; D009154:Mutation; D009693:Nucleic Acid Hybridization; D034622:RNA Interference
D019941:Cyclin-Dependent Kinase Inhibitor p16; C512478:EGFR protein, human; D066246:ErbB Receptors; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases