title: The evolution of thymic lymphomas in p53 knockout mice.
abstract: Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors' driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas.
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA;
authors.forename: Crissy
authors.initials: C
authors.lastname: Dudgeon
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA;
authors.forename: Chang
authors.initials: C
authors.lastname: Chan
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA;
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Kang
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Biomarker Discovery, Adaptive Biotechnologies, Seattle, Washington 98102, USA;
authors.forename: Ryan
authors.initials: R
authors.lastname: Emerson
authors.affiliation: Biomarker Discovery, Adaptive Biotechnologies, Seattle, Washington 98102, USA; Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA:
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA; Simons Center for Systems Biology, School of Natural Sciences, Institute for Advanced Study, Princeton, New Jersey 08540, USA alevine@ias.edu.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
mesh_terms: D000818:Animals; D056741:Cyclin D / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D056915:DNA Copy Number Variations; D019143:Evolution, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008223:Lymphoma / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D056741:Cyclin D; D016159:Tumor Suppressor Protein p53; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Pten; T-cell lymphoma; chromosome abnormalities; clonality; mutation rate; p53