Klumb Claudete Esteves, Furtado Daniel Rodrigues, de Resende Lídia Maria Magalhães, Carriço Maria Kadma, Coelho Arthur Moellman, de Meis Ernesto, Maia Raquel Ciuvalschi, Rumjanek Franklin David
Laboratório de Hematologia Celular e Molecular, Hospital do Câncer/Instituto Nacional de Câncer, Universidade Federal do Rio de Janeiro, Brazil.
Eur J Haematol. 2003 Aug;71(2):81-90. doi: 10.1034/j.1600-0609.2003.00094.x.
The TP53 gene encodes a nuclear protein implicated in the regulation of the cell cycle, DNA repair, and apoptosis. TP53 mutations and other alterations have been described in numerous types of tumors, and some of these have been associated with poor prognosis. The aim of this study was to characterize TP53 mutations in childhood B non-Hodgkin's lymphoma, their correlation with clinical prognostic factors and response to therapy.
Samples from 49 children with B non-Hodgkin's lymphoma were examined for TP53 alterations by single-strand conformation polymorphism analysis (SSCP) of exons 5-9, direct sequencing and by p53 immunohistochemistry.
Mutations of TP53 were detected in 11 of 49 (22.5%) patients and more specifically in 20% of Burkitt's lymphoma. The sequence analysis showed missense mutations in 10 cases and an insertion mutation in one case. Mutations of the transition type occurred more frequently than transversions (seven of 11). Analysis of the spectrum of single-nucleotide substitutions showed a 30% frequency of transition mutations in CpG dinucleotide sequences. The overall frequency of p53 immunostaining positivity was 36% (15 of 41). There was a very good agreement between protein expression and the presence of TP53 mutation (P=0.0005). No significant correlation was found regarding age, gender, clinical stage and LDH level and TP53 mutations. Comparison of EFS curves using the log-rank test were also not significant. However, the analysis of the effects of mutations on the core p53 structure identified biological and biochemical mutants with phenotypes probably related to different response to chemotherapy.
Our data suggest that some types of mutants can alter the protein distinctly and may be associated with a more aggressive phenotype. In addition, the impact of TP53 mutations on response to therapy may also be influenced by disruption of other genes.
TP53基因编码一种核蛋白，参与细胞周期调控、DNA修复及细胞凋亡过程。TP53突变及其他改变已在多种肿瘤类型中被描述，其中一些与预后不良相关。本研究旨在明确儿童B细胞非霍奇金淋巴瘤中TP53突变的特征、其与临床预后因素的相关性以及对治疗的反应。
对49例儿童B细胞非霍奇金淋巴瘤患者的样本进行检测，采用外显子5 - 9的单链构象多态性分析（SSCP）、直接测序及p53免疫组化检测TP53改变。
49例患者中有11例（22.5%）检测到TP53突变，其中伯基特淋巴瘤患者中突变率为20%。序列分析显示10例为错义突变，1例为插入突变。转换型突变比颠换型突变更常见（11例中有7例）。单核苷酸替代谱分析显示，CpG二核苷酸序列中转换突变频率为30%。p53免疫染色阳性的总体频率为36%（41例中有15例）。蛋白表达与TP53突变的存在之间存在非常好的一致性（P = 0.0005）。未发现年龄、性别、临床分期及乳酸脱氢酶水平与TP53突变之间存在显著相关性。使用对数秩检验比较无事件生存期曲线也无显著差异。然而，对突变对核心p53结构影响的分析确定了生物学和生化突变体，其表型可能与对化疗的不同反应相关。
我们的数据表明，某些类型的突变体可明显改变蛋白质，可能与更具侵袭性的表型相关。此外，TP53突变对治疗反应的影响也可能受其他基因破坏的影响。
