Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas

George Vasmatzis, Sarah H. Johnson, Ryan A. Knudson, Rhett P. Ketterling, Esteban Braggio, Rafael Fonseca, David S. Viswanatha, Mark E. Law, N. Sertac Kip, Nazan Özsan, Stefan K. Grebe, Lori A. Frederick, Bruce W. Eckloff, E. Aubrey Thompson, Marshall E. Kadin, Dragana Milosevic, Julie C. Porcher, Yan W. Asmann, David I. Smith, Irina V. KovtunStephen M. Ansell, Ahmet Dogan, Andrew L. Feldman

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124 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2280-2289
Number of pages10
JournalBlood
Volume120
Issue number11
DOIs
StatePublished - Sep 13 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Vasmatzis, G., Johnson, S. H., Knudson, R. A., Ketterling, R. P., Braggio, E., Fonseca, R., Viswanatha, D. S., Law, M. E., Kip, N. S., Özsan, N., Grebe, S. K., Frederick, L. A., Eckloff, B. W., Thompson, E. A., Kadin, M. E., Milosevic, D., Porcher, J. C., Asmann, Y. W., Smith, D. I., ... Feldman, A. L. (2012). Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood, 120(11), 2280-2289. https://doi.org/10.1182/blood-2012-03-419937