A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions
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Xue-2012-A cluster of coopera.pdf
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Author(s)
Xue, Wen
Kitzing, Thomas
Roessler, Stephanie
Zuber, Johannes
Krasnitz, Alexander
Schultz, Nikolaus
Revill, Kate
Weissmueller, Susann
Rappaport, Amy R.
Simon, Janelle
Date Issued
May 2012
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
Xue, W. et al. “A Cluster of Cooperating Tumor-suppressor Gene Candidates in Chromosomal Deletions.” Proceedings of the National Academy of Sciences 109.21 (2012): 8212–8217. Web.© 2012 National Academy of Sciences.
Version
Final published version
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
http://dx.doi.org/10.1073/pnas.1206062109
