CORRELATION BETWEEN MUTATION IN P53, P53 EXPRESSION, CYTOGENETICS, HISTOLOGIC TYPE, AND SURVIVAL IN PATIENTS WITH B-CELL NON-HODGKINS-LYMPHOMA

In the biology of a cell, the central role of p53 in controlling funct ions such as Oils transition (check point) and DNA damage repair, and as a trigger of apoptosis, is well established. Somatic mutations or o ther 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 l ymphomas (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 imm unostaining. On Southern blots, no gross change was identified in P53 and no mutation was identified in exon 9. In exons 5 through 8, 27 dif ferent mutations were identified in 25 patients (23 single-base substi tutions, 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 (FS CCs), 2 of 35 follicular mixed small cleaved-cell and large-cell lymph omas (FMxs), 1 of 4 follicular large-cell lymphomas (FLCs), 1 of 14 di ffuse small cleaved-cell lymphomas (DSCCs), 2 of 17 diffuse mixed smal l-and large-cell lymphomas (DMxs), and 16 of 84 diffuse large-cell lym phomas (DLCCs); the difference between the histologic groups was signi ficant (P < .01). Among mantle-cell lymphoma (MC) patients, 3 of 10 ha d mutations. In 16 patients, the mutation was identified in specimens obtained at diagnosis. Mutation of transition type and transversion ty pe occurred at a relative frequency of 2:1. Thirty percent occurred at CpG dinucleotide sequences and the codon for arginine was most freque ntly affected. Nineteen of 99 tumors with complex cytogenetic abnormal ities, but none of 69 tumors with simple cytogenetic abnormalities, ha d 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 p5 3 expression (P < .001), between missense type mutations and p53 expre ssion (P < .005), and between 17p abnormalities and p53 expression (P < .05). Twenty-two of 49 patients without mutation and 14 of 17 patien ts with mutations died (P < .05), but there was no significant differe nce 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 associ ated with a fatal outcome. These findings indicate that in B-NHL. soma tic changes in p53 were present in diagnostic specimens of all histolo gic types, but at a higher frequency in DLC and Me tumors. P53 mutatio n and/or expression has a negative influence on survival, and therefor e can serve as prognostic indicators. Immunostaining for p53 is an eff ective way to screen for P53 changes in these tumors. (C) 1997 by The American Society of Hematology.