Complex analysis of the TP53 tumor suppressor in mantle cell and diffuse large B-cell lymphomas

Abstract

Mutations and deletions of the tumor suppressor TP53 gene are the most frequent genetic alterations detected in human tumors, though they are rather less frequent in lymphomas. However, acquisition of the TP53 mutation was demonstrated to be one of the characteristic markers in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) and prognostic value of the TP53 status has been recognized for these diseases. We present the complex analysis of the TP53 aberrations in 57 cases of MCL and 131 cases of DLBCL. The TP53 status was determined by functional analyses in yeast (FASAY) followed by cDNA and gDNA sequencing. The level of the p53 protein was assessed by immunoblotting and loss of the TP53-specific locus 17p13.3 was detected by FISH. Altogether, we detected 13 TP53 mutations among MCL cases (22.8%) and 29 TP53 mutations in 26 from 131 DLBCL cases (19.8%). The ratio of missense TP53 mutations was 76.9% in MCL and 82.8% in DLBCL. The frequency of TP53 locus deletion was rather low in both diseases, reaching 9.3% in MCL and 15.3% in DLBCL. The presence of TP53 mutation was associated with shorter overall survival (OS) and progression-free survival (PFS) in MCL. Among DLBCL cases, the TP53 mutations shortened both OS and PFS of patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and decreased both OS and PFS of patients with secondary DLBCL disease.

Comparative High-Resolution Transcriptome Sequencing of Lymphoma Cell Lines and de novo Lymphomas Reveals Cell-Line-Specific Pathway Dysregulation

“…Inactivation or functional alternation of p53 by genomic loss or modulating mutations are frequently observed in human hematopoietic neoplasias including DLBCLs. Thereby, loss or mutation of p53 correlates with chemo resistance, shorter overall as well as progression free survival 38 . Consequently, the herein observed downregulation in the cell lines indicated a selection of an aggressive clone within the cell line compared to the primary samples.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from September–August 2017

“…The authors suggest that patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents. Zlamalikova et al [ 37 ] add significant data to this work. They present the complex analysis of the TP53 aberrations in 57 cases of MCL and 131 cases of DLBCL.…”

Prognostic significance of p53, Sox11, and Pax5 co-expression in mantle cell lymphoma

“…However, Greiner et al assessed p53 expression at the protein level in MCL patients, but only reported correlation between TP53 mutations and the patients’ OS 7 . Stefancikova and Zlamalikova et al also were unable to find relevance between expression of p53 protein and MCL prognosis 26 , 27 . Thus, the single antigen expression of p53, Sox11, or Pax5 might not be sufficient to predict MCL prognosis.…”