title: Inactivation of tumor suppressor genes: choice between genetic and epigenetic routes.
abstract: Inactivation of tumor suppressor genes can occur via epigenetic or genetic mechanisms. The reasons underlying this choice of gene inactivation routes during tumorigenesis have not been clarified, nor have the precise roles in cancer evolution for genes which are solely affected by epigenetically mediated loss of function. Here we discuss a mouse model in which the disruption of Hic1, a gene solely involved with epigenetic silencing in human cancer, can markedly influence the disruption of the powerful tumor suppressor gene, p53, in determining malignant tumor incidence, spectrum and virulence. Furthermore, the mechanism for inactivation of Hic1 in tumors produced can be switched from an epigenetic to a genetic mode depending on how the Hic1 and p53 knockouts are localized on mouse chromosome 11. The value of such a model and the implications of the findings for choice of epigenetically versus genetically determined loss of gene function in cancer are discussed.
authors.affiliation: Cancer Biology Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Wen Yong
authors.initials: WY
authors.lastname: Chen
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000502:physiology; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors