P53 GENE-MUTATIONS AND PROTEIN OVEREXPRESSION ARE ASSOCIATED WITH AGGRESSIVE VARIANTS OF MANTLE CELL LYMPHOMAS

Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearr angement and cyclin D1/PRAD-1 gene overexpression. Some aggressive var iants have been recognized with a blastic or large cell morphology, hi gher proliferative activity, and shorter survival. p53 gene mutations in lymphoid neoplasms have been detected mainly in high grade lymphoma s and have been associated with tumor progression in follicular and sm all lymphocytic lymphomas. To determine the role of p53 alterations in MCL, we examined 35 typical and 8 aggressive variants (5 blastic and 3 large cell) of MCLs by a combination of immunohistochemistry. single -strand conformational polymorphism analysis of genomic DNA and/or cDN A obtained by reverse transcriptase-polymerase chain reaction, denatur ing gradient gel electrophoresis, and sequencing. Of the 8 aggressive MCLs, 3 (38%) contained missense point mutations in exon 8 codon 278 ( Pro --> Leu), exon 8 codon 273 (Arg --> His), and exon 5 codon 151 (Pr o --> Ser), respectively. A diffuse p53 protein overexpression was obs erved in more than 50% of the tumor cells in these 3 cases. A fourth b lastic MCL also showed strong p53 immunoreactivity. However, no mutati ons were detected in exons 5-9 in this case. p53 expression was also d etected in 10% of the cells in an additional large cell type of MCL an d in less than 1% of the cells in 6 typical cases. No mutations were d etected in any of these cases or in the remaining cases with no expres sion of the protein. Four nucleotide changes were observed by single-s trand conformational polymorphism analysis in 4 typical MCLs with no o verexpression of the protein. Direct sequencing showed that these nucl eotide changes were located at exon 6 (1 case), intron 7 (2 cases), an d intron 8 (1 case). The changes in exon 6 and intron 7 were known pol ymorphisms. The nucleotide change in intron 8 was outside splicing sit es of the neighboring exons. The overall survival of the 3 patients wi th p53 mutations (median, 18.3 months) was significantly shorter than that of pateints with the nonmutated MCLs (median, 49 months; P < .01) . These findings indicate that p53 gene mutations are an infrequent ph enomenon in MCLs and are associated with a subset of aggressive varian ts. This is a US government work. There are no restrictions on its use .