p53 Mutations in Nasal Natural Killer/T-Cell Lymphoma from Mexico

Abstract

Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus, and with a characteristic geographic distribution. Recently, we showed that p53 is overexpressed in a high percentage of nasal NK/T-cell lymphomas. The aim of this study was to analyze the status of the p53 gene, and correlate it with the expression of p53 protein and its downstream target, the cyclin-dependent kinase inhibitor p21, in a series of 25 cases of well-characterized nasal NK/T-cell lymphoma from Mexico. The highly conserved exons 5 to 8 of the p53 gene were amplified by polymerase chain reaction and screened for mutations by denaturing high-pressure liquid chromatography. Abnormal polymerase chain reaction products detected by denaturing high-pressure liquid chromatography and additional selected cases were sequenced. In addition, the incidence of loss of heterozygosity at the p53 locus was analyzed in 12 cases. Of the 25 patients, 17 were male and 8 female (M:F ratio, 2.1:1), with a median age of 43 years (range, 21 to 93 years). Morphologically, most of the cases were composed of a mixture of medium-sized cells and large transformed cells (21 cases), and four cases were composed exclusively of large transformed cells. Three different groups determined by p53 gene status and expression of p53 protein were identified: group 1 was p53 +/p53 mutated (five cases, all with p53 missense mutations). Morphologically, three of the five cases were composed of large cells. All five cases revealed overexpression of p53 in the majority of the tumor cells with a mean of 86%. Unexpectedly, three of these cases also showed overexpression of p21. Four of the five patients presented with clinical stage IVB and died with disease. Group 2 was p53+/p53 wild-type (10 cases). Histologically, nine cases were of the mixed type, and one of the large cell type. The percentage of p53 overexpressing cells was lower than in the previous group with a mean of 23%. p21 was positive in 7 of the 10 cases. Six patients in this group presented with clinical stages I to II and four patients with advanced disease (stage III and IV). Five patients are alive 12 to 120 months later (mean, 24 months), three with no evidence of disease. Group 3 was p53-/p53 wild-type (10 cases). All cases showed mixed cell morphology. p21 was positive in 5 of 10 cases. Four patients presented with clinical stage I to II and six patients with advanced disease. Four patients are alive with no evidence of disease 9 to 60 months later (mean, 10 months). Overall, p53 mutations were present in 24% (5 of 21) of the evaluable cases, all of them overexpressing p53 in the majority of tumor cells. Cases with p53 mutations were associated with large cell morphology (P = 0.0162) and presented more often with advanced stage disease. Loss of heterozygosity at chromosome 17p was found only in 2 of the 12 (17%) cases investigated, both cases showed p53 mutations of the remaining allele. P21 overexpression (60% of cases) is frequent in nasal NK/T-cell lymphoma and seems to be indepe...

Mutational Analysis of Extranodal NK/T-Cell Lymphoma Using Targeted Sequencing with a Comprehensive Cancer Panel

“…We found a mutation in TP53 in one out of the five cases. Mutations in TP53 have been described in NKTCL at various proportions, suggesting some racial, environmental, or lifestyle differences as a possible cause of tumorigenesis, and appear to correlate with more advanced-stage disease [ 31 32 33 ]. In other lymphoma studies using NGS, including pediatric Burkitt lymphoma and mantle cell lymphoma, mutations in TP53 were also frequently found [ 26 29 ].…”

Epstein–Barr virus-associated lymphomas

“…Of particular note, loss of proteins such as FOXO3 and HACE1 may contribute to the apoptosis-resistance phenotype of EBV+ T/NK LPD by, respectively, preventing the induction of the pro-apoptotic BIM and PUMA, and by impairing TNF-driven NF-κB activation. Several recent studies have also identified activating mutations in STAT3 and STAT5B in up to 15% of ENKT lymphomas [ 142 , 143 ] and activating mutations in JAK have been variously observed [ 144 ]. Notably, all the STAT3 and STAT5B mutations were located in the SH2 domain, which is critical for STAT activation, and resulted in increased STAT phosphorylation, robust promotion of cell growth and cell survival under IL-2 limiting concentrations.…”

CD56-Negative Aggressive NK Cell Leukemia Relapsing as Multiple Cranial Nerve Palsies: Case Report and Literature Review

“…For instance, genes located at 17p13.1 include those codifying for the aurora kinase B (AURKB), a centrosome-associated kinase that plays an important role as regulator of chromosome segregation and cytokinesis, and, for the tumor protein p53, a protein that causes cells with damaged DNA to arrest at the G1 phase of cell cycle (TP53). Deletions on TP53 , a tumor suppressor gene, are frequently found in neoplastic NK cells and have been associated with more advanced disease, suggesting a secondary oncogenic event rather than a triggering mechanism [ 38 ]. In addition, genes located at the 19q13 are the BAX and BCL3 apoptosis related genes [ 39 ], genes involved in cell cycle progression that codify for cyclins, such as CCNE1 , and genes codifying for transcription factors, such as FOSB [ 40 ], among others [ 41 ].…”