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Open Access 01-12-2016 | Research

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

Authors: Helga D. Munch-Petersen, Fazila Asmar, Konstantinos Dimopoulos, Aušrinė Areškevičiūtė, Peter Brown, Mia Seremet Girkov, Anja Pedersen, Lene D. Sjö, Steffen Heegaard, Helle Broholm, Lasse S. Kristensen, Elisabeth Ralfkiaer, Kirsten Grønbæk

Published in: Acta Neuropathologica Communications | Issue 1/2016

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.

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Title: TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy
Authors: Helga D. Munch-Petersen
Fazila Asmar
Konstantinos Dimopoulos
Aušrinė Areškevičiūtė
Peter Brown
Mia Seremet Girkov
Anja Pedersen
Lene D. Sjö
Steffen Heegaard
Helle Broholm
Lasse S. Kristensen
Elisabeth Ralfkiaer
Kirsten Grønbæk
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2016
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-016-0307-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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