The Prognostic Value of TP53 Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and Chemorefractoriness
The Prognostic Value of TP53 Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and Chemorefractoriness
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DOI：
10.1158/1078-0432.ccr-08-1630
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发表时间：
2009-02-01
影响因子：
11.5
通讯作者：
Gaidano, Gianluca
中科院分区：
文献类型：
--
作者：
Rossi, Davide;Cerri, Michaela;Gaidano, Gianluca
目的：Del17 p13基因可预测慢性淋巴细胞白血病（CLL）的不良预后和化疗难治性。相反，目前尚不清楚TP53突变是否具有独立于del17p13的预后价值。我们测试了TP53突变在CLL中的独立预后价值。实验设计：该研究基于308例CLL的连续系列。在CLL诊断时进行TP53外显子2至10的DNA测序和del17p13间期荧光原位杂交。研究终点为生存率和化疗难治性。结果：在诊断时，TP53突变（n = 32）发生在31/308（10.0%）的患者。在所有显示TP 53突变和/或缺失破坏的CLL中（n = 44），10例（22.7%）显示TP 53突变而缺失del 17 p13。多变量分析选择TP53突变（风险比，3.20; P = 0.002）作为校正del17p13后总生存率的独立预测因子。此外，多变量分析选择TP53突变（风险比，3.97; P <0.001）作为校正del7p13后化疗无效性的独立预测因子。与没有TP53改变的病例相比，携带任何类型的TP53破坏（仅突变，仅del7p13，或突变和del17p13）的CLL均显示出不利的突变和不良结局的高患病率。连续CLL样品的分析显示，在化疗难治性时获得新的或额外的TP53改变。结论：这些数据表明（a）TP 53突变是短生存期和化疗难治性的独立预测因子，和（B）呈现TP 53突变而无del17 p13的CLL与携带del17 p13的CLL一样差。由于携带TP53突变而没有dell7p13的CLL目前不被常规诊断策略识别，因此这些结果可能与CLL的综合预后表征相关。
Purpose: Del17p13 predicts poor outcome and chemorefractoriness in chronic lymphocytic leukemia (CLL). Conversely, it is unknown whether TP53 mutations carry any prognostic value independent of del17p13. We tested the independent prognostic value of TP53 mutations in CLL. Experimental Design: The study was based on a consecutive series of 308 CLL. DNA sequencing of TP53 exons 2 to 10 and del17p13 interphase fluorescence in situ hybridization were done at CLL diagnosis. Study end points were survival and chemorefractoriness. Results: At diagnosis, TP53 mutations (n = 32) occurred in 31 of 308 (10.0%) patients. Of all CLL showing TP53 disruption by either mutation and/or deletion (n = 44), 10 cases (22.7%) showed TP53 mutations in the absence of del17p13. Multivariate analysis selected TP53 mutations (hazard ratio, 3.20; P = 0.002) as an independent predictor of overall survival after adjustment for del17p13. Also, multivariate analysis selected TP53 mutations (hazard ratio, 3.97; P < 0.001) as an independent predictor of chemorefractoriness after adjustment for del7p13. Compared with cases without TP53 alterations, CLL harboring any type of TP53 disruption (mutation only, del7p13 only, or both mutation and del17p13) uniformly displayed a high prevalence of unfavorable prognosticators and poor outcome. Analysis of sequential CLL samples showed the acquisition of new or additional TP53 alterations at the time of chemorefractoriness. Conclusions: These data show that (a) TP53 mutations are an independent predictor of short survival and chemorefractoriness, and (b) that CLL presenting with TP53 mutations without del17p13 fare as poorly as CLL carrying del17p13. Because CLL harboring TP53 mutations without dell7p13 are currently not recognized by conventional diagnostic strategies, these results may be relevant for a comprehensive prognostic characterization of CLL.