TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.
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.
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.|Department of Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Helga D
HD
Munch-Petersen
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Fazila
F
Asmar
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Konstantinos
K
Dimopoulos
Department of Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Aušrinė
A
Areškevičiūtė
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Peter
P
Brown
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Mia Seremet
MS
Girkov
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Anja
A
Pedersen
Department of Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Lene D
LD
Sjö
Department of Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.|Department of Ophtalmology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Steffen
S
Heegaard
Department of Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Helle
H
Broholm
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
Lasse S
LS
Kristensen
Department of Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Elisabeth
E
Ralfkiaer
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Department 3733, Copenhagen Biocenter, Building 2, 3rd floor, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark. kirsten.groenbaek@regionh.dk.
Kirsten
K
Grønbæk
D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D019175:DNA Methylation / Q000235:genetics; D004252:DNA Mutational Analysis; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism; D003718:Denmark; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010597:Pharmacogenetics; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D015703:Antigens, CD; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases
DNA methylation; Hotspot mutations; MIR34A; PCNSL; Survival; TP53