English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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-TP53 in 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.   Electronic supplementary material  The online version of this article (doi:10.1186/s40478-016-0307-6) contains supplementary material, which is available to authorized users.

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