title: The Evolution of Tumors in Mice and Humans with Germline p53 Mutations.
abstract: Mice with a homozygous p53 gene deletion develop thymic lymphomas by 9 wk of age. Using the sequence of the rearranged T-cell receptor gene from each clone of cells in the thymus, one can determine the number of independent transformation events. These tumors are oligoclonal, occurring at a frequency of 0.13-0.8 new cancer clones per day. By 20 wk only a few clones are detected, indicating competition among transformed cell clones. DNA sequencing of these tumors demonstrates a point mutation frequency of one per megabase and many genes that are consistently amplified or deleted in independent tumors. The tumors begin with an inherited p53 gene deletion. Next is a PTEN mutation in a stem cell or progenitor cell, before the rearrangement of the T-cell receptor. After that, the T-cell clone selects gene amplifications in cyclin D and cdk-6, and in Ikaros in the Notch pathway. Humans heterozygous for the p53 mutant gene in the germline (Li-Fraumeni syndrome) develop cancers at an early age. The penetrance of heterozygous p53 mutations is ∼93% of individuals developing tumors over their lives. At older ages the remaining 7% of this Li-Fraumeni population actually have a lower risk of developing tumors than the population at large with wild-type p53 genes.
authors.affiliation: Institute for Advanced Study, Princeton, New Jersey 08540 Cancer Institute of New Jersey, New Brunswick, New Jersey 08903.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Cancer Institute of New Jersey, New Brunswick, New Jersey 08903 Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Jersey 08903.
authors.forename: Chang S
authors.initials: CS
authors.lastname: Chan
authors.affiliation: Cancer Institute of New Jersey, New Brunswick, New Jersey 08903.
authors.forename: Crissy
authors.initials: C
authors.lastname: Dudgeon
authors.affiliation: Cancer Institute of New Jersey, New Brunswick, New Jersey 08903.
authors.forename: Anna
authors.initials: A
authors.lastname: Puzio-Kuter
authors.affiliation: Grenoble Institute for Research on Cancer, Grenoble 38706, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000818:Animals; D056741:Cyclin D / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D005784:Gene Amplification; D015329:Gene Rearrangement, T-Lymphocyte; D019672:Genes, T-Cell Receptor; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D056741:Cyclin D; D016159:Tumor Suppressor Protein p53; D051740:Ikaros Transcription Factor; D051361:Cyclin-Dependent Kinase 6; D051059:PTEN Phosphohydrolase