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 D 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 Asmann, David I Smith, Irina V KovtunStephen Maxted Ansell, Ahmet Dogan, Andrew L Feldman

Research output: Contribution to journalArticle

123 Citations (Scopus)

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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Peripheral T-Cell Lymphoma
T-cells
p53 Genes
Genes
Genome
Cells
Neoplasms
Lymphoma, Large B-Cell, Diffuse
Computational Biology
Gene Library
Bioinformatics
Molecular Biology
Protein Isoforms
Survival Rate
Tumors
Fusion reactions
T-Lymphocytes
Cell Line
Mutation
Tissue

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. / Vasmatzis, George; Johnson, Sarah H.; Knudson, Ryan A.; Ketterling, Rhett P.; Braggio, Esteban D; Fonseca, Rafael; Viswanatha, David S.; Law, Mark E.; Kip, N. Sertac; Özsan, Nazan; Grebe, Stefan K.; Frederick, Lori A.; Eckloff, Bruce W.; Thompson, E Aubrey; Kadin, Marshall E.; Milosevic, Dragana; Porcher, Julie C.; Asmann, Yan; Smith, David I; Kovtun, Irina V; Ansell, Stephen Maxted; Dogan, Ahmet; Feldman, Andrew L.

In: Blood, Vol. 120, No. 11, 13.09.2012, p. 2280-2289.

Research output: Contribution to journalArticle

Vasmatzis, G, Johnson, SH, Knudson, RA, Ketterling, RP, Braggio, ED, Fonseca, R, Viswanatha, DS, Law, ME, Kip, NS, Özsan, N, Grebe, SK, Frederick, LA, Eckloff, BW, Thompson, EA, Kadin, ME, Milosevic, D, Porcher, JC, Asmann, Y, Smith, DI, Kovtun, IV, Ansell, SM, Dogan, A & Feldman, AL 2012, 'Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas', Blood, vol. 120, no. 11, pp. 2280-2289. https://doi.org/10.1182/blood-2012-03-419937
Vasmatzis, George ; Johnson, Sarah H. ; Knudson, Ryan A. ; Ketterling, Rhett P. ; Braggio, Esteban D ; Fonseca, Rafael ; Viswanatha, David S. ; Law, Mark E. ; Kip, N. Sertac ; Özsan, Nazan ; Grebe, Stefan K. ; Frederick, Lori A. ; Eckloff, Bruce W. ; Thompson, E Aubrey ; Kadin, Marshall E. ; Milosevic, Dragana ; Porcher, Julie C. ; Asmann, Yan ; Smith, David I ; Kovtun, Irina V ; Ansell, Stephen Maxted ; Dogan, Ahmet ; Feldman, Andrew L. / Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. In: Blood. 2012 ; Vol. 120, No. 11. pp. 2280-2289.
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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.",
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AU - Vasmatzis, George

AU - Johnson, Sarah H.

AU - Knudson, Ryan A.

AU - Ketterling, Rhett P.

AU - Braggio, Esteban D

AU - Fonseca, Rafael

AU - Viswanatha, David S.

AU - Law, Mark E.

AU - Kip, N. Sertac

AU - Özsan, Nazan

AU - Grebe, Stefan K.

AU - Frederick, Lori A.

AU - Eckloff, Bruce W.

AU - Thompson, E Aubrey

AU - Kadin, Marshall E.

AU - Milosevic, Dragana

AU - Porcher, Julie C.

AU - Asmann, Yan

AU - Smith, David I

AU - Kovtun, Irina V

AU - Ansell, Stephen Maxted

AU - Dogan, Ahmet

AU - Feldman, Andrew L

PY - 2012/9/13

Y1 - 2012/9/13

N2 - 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.

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