Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: An international collaborative study

Ken H. Young, Karen Leroy, Michael B. Møller, Gisele W B Colleoni, Margarita Sánchez-Beato, Fábio R. Kerbauy, Corinne Haioun, Jens C. Eickhoff, Allen H. Young, Philippe Gaulard, Miguel A. Piris, Terry D. Oberley, William M. Rehrauer, Brad S. Kahl, James S. Malter, Elias Campo, Jan Delabie, Randy D. Gascoyne, Andreas Rosenwald, Lisa RimszaJames Huang, Rita M. Braziel, Elaine S. Jaffe, Wyndham H. Wilson, Louis M. Staudt, Julie Marie Vose, Wing C. Chan, Dennis D. Weisenburger, Timothy Charles Greiner

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P=.002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.

Original languageEnglish (US)
Pages (from-to)3088-3098
Number of pages11
JournalBlood
Volume112
Issue number8
DOIs
StatePublished - Oct 15 2008

Fingerprint

Lymphoma, Large B-Cell, Diffuse
p53 Genes
Genes
Cells
Mutation
DNA
Survival
B-Lymphocytes
Germinal Center
Missense Mutation
Multivariate Analysis

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma : An international collaborative study. / Young, Ken H.; Leroy, Karen; Møller, Michael B.; Colleoni, Gisele W B; Sánchez-Beato, Margarita; Kerbauy, Fábio R.; Haioun, Corinne; Eickhoff, Jens C.; Young, Allen H.; Gaulard, Philippe; Piris, Miguel A.; Oberley, Terry D.; Rehrauer, William M.; Kahl, Brad S.; Malter, James S.; Campo, Elias; Delabie, Jan; Gascoyne, Randy D.; Rosenwald, Andreas; Rimsza, Lisa; Huang, James; Braziel, Rita M.; Jaffe, Elaine S.; Wilson, Wyndham H.; Staudt, Louis M.; Vose, Julie Marie; Chan, Wing C.; Weisenburger, Dennis D.; Greiner, Timothy Charles.

In: Blood, Vol. 112, No. 8, 15.10.2008, p. 3088-3098.

Research output: Contribution to journalArticle

Young, KH, Leroy, K, Møller, MB, Colleoni, GWB, Sánchez-Beato, M, Kerbauy, FR, Haioun, C, Eickhoff, JC, Young, AH, Gaulard, P, Piris, MA, Oberley, TD, Rehrauer, WM, Kahl, BS, Malter, JS, Campo, E, Delabie, J, Gascoyne, RD, Rosenwald, A, Rimsza, L, Huang, J, Braziel, RM, Jaffe, ES, Wilson, WH, Staudt, LM, Vose, JM, Chan, WC, Weisenburger, DD & Greiner, TC 2008, 'Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: An international collaborative study', Blood, vol. 112, no. 8, pp. 3088-3098. https://doi.org/10.1182/blood-2008-01-129783
Young, Ken H. ; Leroy, Karen ; Møller, Michael B. ; Colleoni, Gisele W B ; Sánchez-Beato, Margarita ; Kerbauy, Fábio R. ; Haioun, Corinne ; Eickhoff, Jens C. ; Young, Allen H. ; Gaulard, Philippe ; Piris, Miguel A. ; Oberley, Terry D. ; Rehrauer, William M. ; Kahl, Brad S. ; Malter, James S. ; Campo, Elias ; Delabie, Jan ; Gascoyne, Randy D. ; Rosenwald, Andreas ; Rimsza, Lisa ; Huang, James ; Braziel, Rita M. ; Jaffe, Elaine S. ; Wilson, Wyndham H. ; Staudt, Louis M. ; Vose, Julie Marie ; Chan, Wing C. ; Weisenburger, Dennis D. ; Greiner, Timothy Charles. / Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma : An international collaborative study. In: Blood. 2008 ; Vol. 112, No. 8. pp. 3088-3098.
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abstract = "The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P=.002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.",
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T1 - Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma

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AU - Young, Ken H.

AU - Leroy, Karen

AU - Møller, Michael B.

AU - Colleoni, Gisele W B

AU - Sánchez-Beato, Margarita

AU - Kerbauy, Fábio R.

AU - Haioun, Corinne

AU - Eickhoff, Jens C.

AU - Young, Allen H.

AU - Gaulard, Philippe

AU - Piris, Miguel A.

AU - Oberley, Terry D.

AU - Rehrauer, William M.

AU - Kahl, Brad S.

AU - Malter, James S.

AU - Campo, Elias

AU - Delabie, Jan

AU - Gascoyne, Randy D.

AU - Rosenwald, Andreas

AU - Rimsza, Lisa

AU - Huang, James

AU - Braziel, Rita M.

AU - Jaffe, Elaine S.

AU - Wilson, Wyndham H.

AU - Staudt, Louis M.

AU - Vose, Julie Marie

AU - Chan, Wing C.

AU - Weisenburger, Dennis D.

AU - Greiner, Timothy Charles

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N2 - The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P=.002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.

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