TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy

Research output: Contribution to journalJournal articleResearch

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TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy. / Munch-Petersen, Helga D; Asmar, Fazila; Dimopoulos, Konstantinos; Areškevičiūtė, Aušrinė; Brown, Peter; Girkov, Mia Seremet; Pedersen, Anja; Sjö, Lene D; Heegaard, Steffen; Broholm, Helle; Kristensen, Lasse S; Ralfkiaer, Elisabeth; Grønbæk, Kirsten.

In: Acta Neuropathologica Communications, Vol. 4, 40, 22.04.2016.

Research output: Contribution to journalJournal articleResearch

Harvard

Munch-Petersen, HD, Asmar, F, Dimopoulos, K, Areškevičiūtė, A, Brown, P, Girkov, MS, Pedersen, A, Sjö, LD, Heegaard, S, Broholm, H, Kristensen, LS, Ralfkiaer, E & Grønbæk, K 2016, 'TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy', Acta Neuropathologica Communications, vol. 4, 40. https://doi.org/10.1186/s40478-016-0307-6

APA

Munch-Petersen, H. D., Asmar, F., Dimopoulos, K., Areškevičiūtė, A., Brown, P., Girkov, M. S., ... Grønbæk, K. (2016). TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy. Acta Neuropathologica Communications, 4, [40]. https://doi.org/10.1186/s40478-016-0307-6

Vancouver

Munch-Petersen HD, Asmar F, Dimopoulos K, Areškevičiūtė A, Brown P, Girkov MS et al. TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy. Acta Neuropathologica Communications. 2016 Apr 22;4. 40. https://doi.org/10.1186/s40478-016-0307-6

Author

Munch-Petersen, Helga D ; Asmar, Fazila ; Dimopoulos, Konstantinos ; Areškevičiūtė, Aušrinė ; Brown, Peter ; Girkov, Mia Seremet ; Pedersen, Anja ; Sjö, Lene D ; Heegaard, Steffen ; Broholm, Helle ; Kristensen, Lasse S ; Ralfkiaer, Elisabeth ; Grønbæk, Kirsten. / TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy. In: Acta Neuropathologica Communications. 2016 ; Vol. 4.

Bibtex

@article{6896ced619924e1b8995be6ec9831d2f,
title = "TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy",
abstract = "Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 {\%}) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 {\%}), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 {\%}), 80/84 (95.2 {\%}), and 70/75 (93.3 {\%}) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.",
keywords = "Analysis of Variance, Antigens, CD, Antineoplastic Combined Chemotherapy Protocols, Central Nervous System Neoplasms, DNA Methylation, DNA Mutational Analysis, Death-Associated Protein Kinases, Denmark, Female, Humans, Lymphoma, Male, MicroRNAs, Mutation, Pharmacogenetics, Predictive Value of Tests, Retrospective Studies, Survival Analysis, Treatment Outcome, Tumor Suppressor Protein p53",
author = "Munch-Petersen, {Helga D} and Fazila Asmar and Konstantinos Dimopoulos and Aušrinė Areškevičiūtė and Peter Brown and Girkov, {Mia Seremet} and Anja Pedersen and Sj{\"o}, {Lene D} and Steffen Heegaard and Helle Broholm and Kristensen, {Lasse S} and Elisabeth Ralfkiaer and Kirsten Gr{\o}nb{\ae}k",
year = "2016",
month = "4",
day = "22",
doi = "10.1186/s40478-016-0307-6",
language = "English",
volume = "4",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BioMed Central Ltd.",

}

RIS

TY - JOUR

T1 - TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy

AU - Munch-Petersen, Helga D

AU - Asmar, Fazila

AU - Dimopoulos, Konstantinos

AU - Areškevičiūtė, Aušrinė

AU - Brown, Peter

AU - Girkov, Mia Seremet

AU - Pedersen, Anja

AU - Sjö, Lene D

AU - Heegaard, Steffen

AU - Broholm, Helle

AU - Kristensen, Lasse S

AU - Ralfkiaer, Elisabeth

AU - Grønbæk, Kirsten

PY - 2016/4/22

Y1 - 2016/4/22

N2 - Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.

AB - Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.

KW - Analysis of Variance

KW - Antigens, CD

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Central Nervous System Neoplasms

KW - DNA Methylation

KW - DNA Mutational Analysis

KW - Death-Associated Protein Kinases

KW - Denmark

KW - Female

KW - Humans

KW - Lymphoma

KW - Male

KW - MicroRNAs

KW - Mutation

KW - Pharmacogenetics

KW - Predictive Value of Tests

KW - Retrospective Studies

KW - Survival Analysis

KW - Treatment Outcome

KW - Tumor Suppressor Protein p53

U2 - 10.1186/s40478-016-0307-6

DO - 10.1186/s40478-016-0307-6

M3 - Journal article

C2 - 27101868

VL - 4

JO - Acta Neuropathologica Communications

JF - Acta Neuropathologica Communications

SN - 2051-5960

M1 - 40

ER -

ID: 173676908