p53 Mutation in B‐Cell Lymphoid Neoplasms with Reference to Oncogene Rearrangements Associated with Chromosomal Translocations

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Abstract
We investigated mutations of the p53 tumor suppressor gene in B‐cell lymphoid neoplasms with reference to oncogene rearrangements associated with specific chromosomal translocations. These included 15 patients with a BCL1/PRAD1 gene rearrangement and/or PRAD1 overexpression, 45 with a BCL2 rearrangement, 2 with a BCL3 rearrangement, 24 with a BCL6 rearrangement, and 6 with both BCL2 and BCL6 rearrangements. Thirty‐six patients lacked detectable oncogene rearrangements. Genomic DNA was isolated from involved tissues or leukemic cells obtained at diagnosis and/or at relapse, and established cell lines. Polymerase chain reaction‐mediated single‐strand conformation polymorphism analysis and direct sequencing were performed to analyze abnormalities of the p53 gene. We detected p53 gene alterations in 18 of 128 patients, representing 21 of the total 151 materials analyzed. In the total of 66 patients with an oncogene rearrangement studied at diagnosis, only one had a mutation; however, 6 of 37 patients studied at relapse showed p53 mutations. Sequential analysis revealed that the p53 mutation was closely associated with transformation from follicular lymphoma to large cell lymphoma, exclusively in BCL2‐positive lymphoma cases. Two of 13 mutations observed in oncogene rearrangement‐positive cases and cell lines were transitions at CpG dinucleotides. In contrast, the relationship between p53 mutations and clinical behavior in oncogene rearrangement‐negative cases was variable; 5 patients including one with indolent follicular lymphoma were positive for p53 mutation at initial presentation, and 2 of the 5 showed prolonged disease‐free survival. Our findings suggest that p53 alteration exhibits diverse functions in the development and progression of B‐cell tumors related to the presence or absence of oncogene rearrangement, and that chemotherapy‐related influences may be involved in the occurrence of progression‐associated p53 mutations.