Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.
The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.
Zender
Lars
L
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Spector
Mona S
MS
Xue
Wen
W
Flemming
Peer
P
Cordon-Cardo
Carlos
C
Silke
John
J
Fan
Sheung-Tat
ST
Luk
John M
JM
Wigler
Michael
M
Hannon
Gregory J
GJ
Mu
David
D
Lucito
Robert
R
Powers
Scott
S
Lowe
Scott W
SW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018797:Cell Cycle Proteins; D016158:Genes, p53; D023281:Genomics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics; D013045:Species Specificity; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C456659:YY1AP1 protein, human; C486223:Yap1 protein, mouse