TP53 Gene Mutations in Tumor Cells of Patients with Aggressive B-Cell Lymphomas

Abstract

Background. TP53 gene mutations impede cell apoptosis and lead to additional oncogenic events contributing to tumor progression. Aim. To assess TP53 gene mutation rate in patients with high-grade B-cell lymphoma double-hit (HGBCL DH) and not otherwise specified (HGBL NOS); to analyse its relationship with disease prognosis. Materials & Methods. Retrospective materials from medical data of 10 HGBL DH and 26 HGBL NOS patients were analyzed. Median follow-up was 26.5 months (range 0.6-160.9 months). Selection was based on the presence of available biological materials (paraffin blocks) for Sanger sequencing of TP53 gene from exon 5 to exon 8 (encoding DNA-binding domain of TP53 gene). FISH analysis of the tumor was performed in all patients to identify translocations involving c-MYC/8q24, BCL2/18q21, and BCL6/3q27 gene locus. To analyze differences between groups χ<sup>2</sup> and Mann-Whitney tests were applied. Univariate event analysis (Kaplan-Meier and log-rank tests) and Cox regression analysis were used to assess the influence of molecular markers on the disease prognosis. Results. TP53 gene mutations in lymphoma cells were found in 13 (36 %) out of 36 patients, 10 (77 %) out of 13 mutations were pathogenic. In 8 out of 10 patients with TP53 mutations c-MYC/8q24 gene translocation was identified. Groups with wild (TP53-WT) and mutant (TP53-MUT) types of TP53 gene were similar in terms of main clinical characteristics. Patients with TP53-MUT in tumor cells showed worse 3-year overall survival (OS) compared with the group without TP53-MUT (30 % vs. 73 %; p = 0.026) as well as higher probability of disease progression in the period of 3 years (66 % vs. 15 %; p = 0.004). In multivariate analysis significant OS predictor was the presence of TP53 mutation (p = 0.006). Relapse/ progression probability was higher in combined cases of TP53 mutation and translocation involving c-MYC gene locus (p = 0.0003). Conclusion. Translocation involving c-MYC gene along with TP53 gene mutation in tumor cells can serve as a criterion for dividing HGBL DH and HGBL NOS patients into different lymphoma relapse/progression risk groups.