Correlation Between Mutation in P53, p53 Expression, Cytogenetics, Histologic Type, and Survival in Patients With B-Cell Non-Hodgkin's Lymphoma

Abstract

In the biology of a cell, the central role of p53 in controlling functions such as G1/S transition (check point) and DNA damage repair, and as a trigger of apoptosis, is well established. Somatic mutations or other changes in P53 have been reported in numerous tumor types, and in some of these, they are associated with poor prognosis. In this study, we examined 237 cytogenetically characterized B-cell non-Hodgkin's lymphomas (B-NHLs) for somatic changes in P53 by Southern blot analysis, by single-strand conformation polymorphism analysis (SSCP) of exon 5 through 9, and by direct sequencing of SSCP variants to determine the frequency and types of mutations and their clinical significance. In a portion of these (173 tumors), we also studied p53 expression by immunostaining. On Southern blots, no gross change was identified in P53 and no mutation was identified in exon 9. In exons 5 through 8, 27 different mutations were identified in 25 patients (23 single-base substitutions, 3 deletions, 1 duplication). Mutations in P53 were identified in 25 of 237 tumors (10.5%), which included 1 of 45 small lymphocytic lymphomas (SLLs), 2 of 38 follicular small cleaved-cell lymphomas (FSCCs), 2 of 35 follicular mixed small cleaved-cell and large-cell lymphomas (FMxs), 1 of 4 follicular large-cell lymphomas (FLCs), 1 of 14 diffuse small cleaved-cell lymphomas (DSCCs), 2 of 17 diffuse mixed small- and large-cell lymphomas (DMxs), and 16 of 84 diffuse large-cell lymphomas (DLCCs); the difference between the histologic groups was significant (P < .01). Among mantle-cell lymphoma (MC) patients, 3 of 10 had mutations. In 16 patients, the mutation was identified in specimens obtained at diagnosis. Mutation of transition type and transversion type occurred at a relative frequency of 2:1. Thirty percent occurred at CpG dinucleotide sequences and the codon for arginine was most frequently affected. Nineteen of 99 tumors with complex cytogenetic abnormalities, but none of 69 tumors with simple cytogenetic abnormalities, had mutations (P < .001). Similarly, 11 of 25 tumors with an abnormality of 17p and 8 of 143 tumors with apparently normal 17p had mutations (P < .0001). Positive correlations were found between a mutation and p53 expression (P < .001), between missense type mutations and p53 expression (P < .005), and between 17p abnormalities and p53 expression (P < .05). Twenty-two of 49 patients without mutation and 14 of 17 patients with mutations died (P < .05), but there was no significant difference in median survival. Similarly, 21 of 26 p53 positive patients died, whereas only 1 of 24 p53-negative patients died on-study (P < .001). Among p53-negative patients, mutation (P < .01) was positively associated with a fatal outcome. These findings indicate that in B-NHL, somatic changes in P53 were present in diagnostic specimens of all histologic types, but at a higher frequency in DLC and MC tumors. P53 mutation and/or expression has a negative influence on survival, and therefore can serve as prognostic indicators. Immunostaining for p53 is an effective way to screen for P53 changes in these tumors.

p53, Mdm2, and c‐Myc overexpression is associated with a poor prognosis in aggressive non‐Hodgkin's lymphomas

“…The p53 tumor suppressor gene is affected in a wide range of human cancers, including hematological malignancies [5][6][7][8][9][10]. In some lymphoid tumors, p53 mutations have been associated with a poor prognosis and with disease progression [11][12][13][14][15][16]. The p53 gene encodes a nuclear phosphoprotein, p53, which plays a key role in cell cycle arrest, induction of apoptosis, and DNA damage repair [17][18].…”

“…It seems that, at the time of diagnosis, 20% B-NHL have somatic mutations in the p53 gene and expression of p53 is remarkably higher among mutated p53, espe-cially when a missense mutation is identified [16]. However, 50% of those with wild type p53 also have a high p53 expression detected by immunohistochemistry.…”

Mutation of p53 Gene and Its Correlation with the Clinical Outcome in Dogs with Lymphoma

“…18 Moreover, it has been shown that NHL patients with p53 mutation also have significantly shorter overall and progressionfree survival time. 18,47 In veterinary medicine, Dhaliwal et al 34 evaluated the expression of P53 using immunohistochemistry in 31 dogs with lymphoma. They reported 7 dogs (22%) to be positive for P53 expression and the expression of P53 was statistically correlated with survival.…”

Simultaneous aberrations of single CDKN2A network components and a high Rb phosphorylation status can differentiate subgroups of primary cutaneous B-cell lymphomas

“…This has been shown to occur regularly in nodal lymphomas with the highest incidence in diffuse large B-cell lymphomas. Certain mutations and p53 expression were associated with a poor survival in distinct subtypes of lymphomas (12). Groenbaeck et al (19), having applied PCR, investigated mis-sense and loss-of-function mutations in the p53 gene also in a small group of diffuse large B-cell lymphomas of the skin (REAL classification) and cutaneous MALT-type lymphomas and found no clear-cut correlation with expression of p53, which was present in 2 ⁄ 6 cases of the former type.…”