A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions.
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Authors
Xue, WenKitzing, Thomas
Roessler, Stephanie
Zuber, Johannes
Krasnitz, Alexander
Schultz, Nikolaus
Revill, Kate
Weissmueller, Susann
Rappaport, Amy R
Simon, Janelle
Zhang, Jack
Luo, Weijun
Hicks, James
Zender, Lars
Wang, Xin Wei
Powers, Scott
Wigler, Michael
Lowe, Scott W
Issue Date
2012-05-22
Metadata
Show full item recordAbstract
The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events.Citation
A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions. 2012, 109 (21):8212-7 Proc. Natl. Acad. Sci. U.S.A.Affiliation
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.PubMed ID
22566646Type
ArticleLanguage
enISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1206062109
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