A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

Xue, W., Kitzing, T., Roessler, S., Zuber, J., Krasnitz, A., Schultz, N., Revill, K., Weissmueller, S., Rappaport, A. R., Simon, J., Zhang, J., Luo, W. J., Hicks, J., Zender, L., Wang, X. W., Powers, S., Wigler, M., Lowe, S. W. (2012) A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions. Proceedings of the National Academy of Sciences of the United States of America, 109 (21). pp. 8212-8217. ISSN 0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/22566646
DOI: 10.1073/pnas.1206062109

Abstract

The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanismin 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.

Item Type: Paper
Uncontrolled Keywords: cancer genomics chromosome 8p deletion RNAi screen human hepatocellular-carcinoma high-resolution analysis liver-cancer copy-number in-vivo breast-cancer arm 8p identification expression reveals
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function > chromosome

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene silencing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > suppressor
CSHL Authors:
Communities: CSHL labs > Hicks lab
CSHL labs > Krasnitz lab
CSHL labs > Lowe lab
CSHL labs > Powers lab
CSHL labs > Wigler lab
Watson School > Publications
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date Deposited: 17 Jan 2013 20:22
Last Modified: 15 Oct 2015 15:14
PMCID: PMC3361457
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27085

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