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PMID: 16814713 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study

Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.

Cell ·Vol. 125 ·No. 7 ·2006-06-30 ·Pages 1253-67

Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Animals Carcinoma, Hepatocellular/genetics Cell Cycle Proteins Genes, p53 Genomics Humans Inhibitor of Apoptosis Proteins/genetics Liver Neoplasms/genetics Liver Neoplasms, Experimental/etiology,genetics,pathology Mice Mice, Knockout Mutation Nuclear Proteins/genetics Oligonucleotide Array Sequence Analysis Oncogenes Phosphoproteins/genetics Species Specificity Trans-Activators/genetics Transcription Factors YAP-Signaling Proteins
Chemicals
Adaptor Proteins, Signal Transducing Cell Cycle Proteins Inhibitor of Apoptosis Proteins Nuclear Proteins Phosphoproteins Trans-Activators Transcription Factors YAP-Signaling Proteins YY1AP1 protein, human Yap1 protein, mouse
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Zender Lars
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Spector Mona S
Xue Wen
Flemming Peer
Cordon-Cardo Carlos
Silke John
Fan Sheung-Tat
Luk John M
Wigler Michael
Hannon Gregory J
Mu David
Lucito Robert
Powers Scott
Lowe Scott W
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/j.cell.2006.05.030
Published
2006-06-30
Pages
1253-67
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3026384
Subset
IM
Grants
NCI NIH HHS · CA13106 · United States
NCI NIH HHS · CA078544 · United States
NCI NIH HHS · R01 CA078544 · United States
NCI NIH HHS · P30 CA008748 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P01 CA087497 · United States
NCI NIH HHS · U01 CA105388 · United States
NCI NIH HHS · P01 CA013106 · United States
NCI NIH HHS · CA105388 · United States
NCI NIH HHS · CA87497 · United States
Corrections
CommentIn
PMID: 16814709
External Links
PubMed source DOI: 10.1016/j.cell.2006.05.030 PMC Full Text View journal details
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