Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP

report from an International DLBCL Rituximab-CHOP Consortium Program Study

Zijun Y Xu-Monette, Lin Wu, Carlo Visco, Yu Chuan Tai, Alexander Tzankov, Wei-min Liu, Santiago Montes-Moreno, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L Richards, Eric D Hsi, X Frank Zhao, William W L Choi, Xiaoying Zhao, J Han van Krieken, Qin Huang, Jooryung Huh & 16 andre Weiyun Ai, Maurilio Ponzoni, Andrés J M Ferreri, Fan Zhou, Brad S Kahl, Jane N Winter, Wei Xu, Jianyong Li, Ronald S Go, Yong Li, Miguel A Piris, Michael B Møller, Roberto N Miranda, Lynne V Abruzzo, L Jeffrey Medeiros, Ken H Young

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.
OriginalsprogEngelsk
TidsskriftBlood
Vol/bind120
Udgave nummer19
Sider (fra-til)3986-96
Antal sider11
ISSN0006-4971
DOI
StatusUdgivet - 2012

Fingeraftryk

Lymphoma, Large B-Cell, Diffuse
Vincristine
Prednisone
Mutation
Nucleotide Motifs
Germinal Center
Disease-Free Survival
Proteins

Citer dette

Xu-Monette, Zijun Y ; Wu, Lin ; Visco, Carlo ; Tai, Yu Chuan ; Tzankov, Alexander ; Liu, Wei-min ; Montes-Moreno, Santiago ; Dybkaer, Karen ; Chiu, April ; Orazi, Attilio ; Zu, Youli ; Bhagat, Govind ; Richards, Kristy L ; Hsi, Eric D ; Zhao, X Frank ; Choi, William W L ; Zhao, Xiaoying ; van Krieken, J Han ; Huang, Qin ; Huh, Jooryung ; Ai, Weiyun ; Ponzoni, Maurilio ; Ferreri, Andrés J M ; Zhou, Fan ; Kahl, Brad S ; Winter, Jane N ; Xu, Wei ; Li, Jianyong ; Go, Ronald S ; Li, Yong ; Piris, Miguel A ; Møller, Michael B ; Miranda, Roberto N ; Abruzzo, Lynne V ; Medeiros, L Jeffrey ; Young, Ken H. / Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP : report from an International DLBCL Rituximab-CHOP Consortium Program Study. I: Blood. 2012 ; Bind 120, Nr. 19. s. 3986-96.
@article{807269b3701b45aababe6b42373469f0,
title = "Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study",
abstract = "TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50{\%} cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.",
keywords = "Adult, Aged, Alleles, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols, Cohort Studies, Computational Biology, Cyclophosphamide, Doxorubicin, Exons, Female, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Loss of Heterozygosity, Lymphoma, Large B-Cell, Diffuse, Male, Middle Aged, Mutation, Mutation Rate, Mutation, Missense, Neoplasm Staging, Prednisone, Prognosis, Treatment Outcome, Tumor Suppressor Protein p53, Vincristine",
author = "Xu-Monette, {Zijun Y} and Lin Wu and Carlo Visco and Tai, {Yu Chuan} and Alexander Tzankov and Wei-min Liu and Santiago Montes-Moreno and Karen Dybkaer and April Chiu and Attilio Orazi and Youli Zu and Govind Bhagat and Richards, {Kristy L} and Hsi, {Eric D} and Zhao, {X Frank} and Choi, {William W L} and Xiaoying Zhao and {van Krieken}, {J Han} and Qin Huang and Jooryung Huh and Weiyun Ai and Maurilio Ponzoni and Ferreri, {Andr{\'e}s J M} and Fan Zhou and Kahl, {Brad S} and Winter, {Jane N} and Wei Xu and Jianyong Li and Go, {Ronald S} and Yong Li and Piris, {Miguel A} and M{\o}ller, {Michael B} and Miranda, {Roberto N} and Abruzzo, {Lynne V} and Medeiros, {L Jeffrey} and Young, {Ken H}",
year = "2012",
doi = "10.1182/blood-2012-05-433334",
language = "English",
volume = "120",
pages = "3986--96",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "19",

}

Xu-Monette, ZY, Wu, L, Visco, C, Tai, YC, Tzankov, A, Liu, W, Montes-Moreno, S, Dybkaer, K, Chiu, A, Orazi, A, Zu, Y, Bhagat, G, Richards, KL, Hsi, ED, Zhao, XF, Choi, WWL, Zhao, X, van Krieken, JH, Huang, Q, Huh, J, Ai, W, Ponzoni, M, Ferreri, AJM, Zhou, F, Kahl, BS, Winter, JN, Xu, W, Li, J, Go, RS, Li, Y, Piris, MA, Møller, MB, Miranda, RN, Abruzzo, LV, Medeiros, LJ & Young, KH 2012, 'Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study', Blood, bind 120, nr. 19, s. 3986-96. https://doi.org/10.1182/blood-2012-05-433334

Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP : report from an International DLBCL Rituximab-CHOP Consortium Program Study. / Xu-Monette, Zijun Y; Wu, Lin; Visco, Carlo; Tai, Yu Chuan; Tzankov, Alexander; Liu, Wei-min; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Zhao, X Frank; Choi, William W L; Zhao, Xiaoying; van Krieken, J Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Zhou, Fan; Kahl, Brad S; Winter, Jane N; Xu, Wei; Li, Jianyong; Go, Ronald S; Li, Yong; Piris, Miguel A; Møller, Michael B; Miranda, Roberto N; Abruzzo, Lynne V; Medeiros, L Jeffrey; Young, Ken H.

I: Blood, Bind 120, Nr. 19, 2012, s. 3986-96.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP

T2 - report from an International DLBCL Rituximab-CHOP Consortium Program Study

AU - Xu-Monette, Zijun Y

AU - Wu, Lin

AU - Visco, Carlo

AU - Tai, Yu Chuan

AU - Tzankov, Alexander

AU - Liu, Wei-min

AU - Montes-Moreno, Santiago

AU - Dybkaer, Karen

AU - Chiu, April

AU - Orazi, Attilio

AU - Zu, Youli

AU - Bhagat, Govind

AU - Richards, Kristy L

AU - Hsi, Eric D

AU - Zhao, X Frank

AU - Choi, William W L

AU - Zhao, Xiaoying

AU - van Krieken, J Han

AU - Huang, Qin

AU - Huh, Jooryung

AU - Ai, Weiyun

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J M

AU - Zhou, Fan

AU - Kahl, Brad S

AU - Winter, Jane N

AU - Xu, Wei

AU - Li, Jianyong

AU - Go, Ronald S

AU - Li, Yong

AU - Piris, Miguel A

AU - Møller, Michael B

AU - Miranda, Roberto N

AU - Abruzzo, Lynne V

AU - Medeiros, L Jeffrey

AU - Young, Ken H

PY - 2012

Y1 - 2012

N2 - TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.

AB - TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.

KW - Adult

KW - Aged

KW - Alleles

KW - Antibodies, Monoclonal, Murine-Derived

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Cohort Studies

KW - Computational Biology

KW - Cyclophosphamide

KW - Doxorubicin

KW - Exons

KW - Female

KW - Gene Deletion

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Loss of Heterozygosity

KW - Lymphoma, Large B-Cell, Diffuse

KW - Male

KW - Middle Aged

KW - Mutation

KW - Mutation Rate

KW - Mutation, Missense

KW - Neoplasm Staging

KW - Prednisone

KW - Prognosis

KW - Treatment Outcome

KW - Tumor Suppressor Protein p53

KW - Vincristine

U2 - 10.1182/blood-2012-05-433334

DO - 10.1182/blood-2012-05-433334

M3 - Journal article

VL - 120

SP - 3986

EP - 3996

JO - Blood

JF - Blood

SN - 0006-4971

IS - 19

ER -