title: Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas.
abstract: Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lymphocytes with 5-year overall survival rates of only ∼ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogenesis of PTCL, with a resulting paucity of molecular targets for therapy. We developed bioinformatic tools to identify chromosomal rearrangements using genome-wide, next-generation sequencing analysis of mate-pair DNA libraries and applied these tools to 16 PTCL patient tissue samples and 6 PTCL cell lines. Thirteen recurrent abnormalities were identified, of which 5 involved p53-related genes (TP53, TP63, CDKN2A, WWOX, and ANKRD11). Among these abnormalities were novel TP63 rearrangements encoding fusion proteins homologous to ΔNp63, a dominant-negative p63 isoform that inhibits the p53 pathway. TP63 rearrangements were seen in 11 (5.8%) of 190 PTCLs and were associated with inferior overall survival; they also were detected in 2 (1.2%) of 164 diffuse large B-cell lymphomas. As TP53 mutations are rare in PTCL compared with other malignancies, our findings suggest that a constellation of alternate genetic abnormalities may contribute to disruption of p53-associated tumor suppressor function in PTCL.
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Johnson
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Knudson
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.forename: David S
authors.initials: DS
authors.lastname: Viswanatha
authors.forename: Mark E
authors.initials: ME
authors.lastname: Law
authors.forename: N Sertac
authors.initials: NS
authors.lastname: Kip
authors.forename: Nazan
authors.initials: N
authors.lastname: Ozsan
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Grebe
authors.forename: Lori A
authors.initials: LA
authors.lastname: Frederick
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Eckloff
authors.forename: E Aubrey
authors.initials: EA
authors.lastname: Thompson
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Kadin
authors.forename: Dragana
authors.initials: D
authors.lastname: Milosevic
authors.forename: Julie C
authors.initials: JC
authors.lastname: Porcher
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.forename: David I
authors.initials: DI
authors.lastname: Smith
authors.forename: Irina V
authors.initials: IV
authors.lastname: Kovtun
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
mesh_terms: D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014481:United States; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: C492515:ANKRD11 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050505:Mutant Proteins; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human