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dc.contributor.authorXue, Wen
dc.contributor.authorKitzing, Thomas
dc.contributor.authorRoessler, Stephanie
dc.contributor.authorZuber, Johannes
dc.contributor.authorKrasnitz, Alexander
dc.contributor.authorSchultz, Nikolaus
dc.contributor.authorRevill, Kate
dc.contributor.authorWeissmueller, Susann
dc.contributor.authorRappaport, Amy R
dc.contributor.authorSimon, Janelle
dc.contributor.authorZhang, Jack
dc.contributor.authorLuo, Weijun
dc.contributor.authorHicks, James
dc.contributor.authorZender, Lars
dc.contributor.authorWang, Xin Wei
dc.contributor.authorPowers, Scott
dc.contributor.authorWigler, Michael
dc.contributor.authorLowe, Scott W
dc.date.accessioned2013-03-06T09:03:42Z
dc.date.available2013-03-06T09:03:42Z
dc.date.issued2012-05-22
dc.identifier.citationA cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions. 2012, 109 (21):8212-7 Proc. Natl. Acad. Sci. U.S.A.en_GB
dc.identifier.issn1091-6490
dc.identifier.pmid22566646
dc.identifier.doi10.1073/pnas.1206062109
dc.identifier.urihttp://hdl.handle.net/10033/271292
dc.description.abstractThe 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.
dc.language.isoenen
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciences of the United States of Americaen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshCarcinoma, Hepatocellularen_GB
dc.subject.meshCell Line, Transformeden_GB
dc.subject.meshCell Line, Tumoren_GB
dc.subject.meshChromosomes, Human, Pair 8en_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGene Deletionen_GB
dc.subject.meshGene Expression Regulation, Neoplasticen_GB
dc.subject.meshGenes, Tumor Suppressoren_GB
dc.subject.meshGenomicsen_GB
dc.subject.meshHaploinsufficiencyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLiveren_GB
dc.subject.meshLiver Neoplasms, Experimentalen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Inbred C57BLen_GB
dc.subject.meshMice, Nudeen_GB
dc.subject.meshMonosomyen_GB
dc.subject.meshRNA Interferenceen_GB
dc.subject.meshStem Cellsen_GB
dc.titleA cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions.en
dc.typeArticleen
dc.contributor.departmentCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.en_GB
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen_GB
refterms.dateFOA2018-06-13T15:18:07Z
html.description.abstractThe 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.


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