University Hospital Brno, Department of Internal Medicine-Hematooncology, Czech Republic.
J Clin Oncol. 2011 Jul 1;29(19):2703-8. doi: 10.1200/JCO.2011.34.7872. Epub 2011 May 23.
There is a distinct connection between TP53 defects and poor prognosis in chronic lymphocytic leukemia (CLL). It remains unclear whether patients harboring TP53 mutations represent a homogenous prognostic group.
We evaluated the survival of patients with CLL and p53 defects identified at our institution by p53 yeast functional assay and complementary interphase fluorescence in situ hybridization analysis detecting del(17p) from 2003 to 2010.
A defect of the TP53 gene was identified in 100 of 550 patients. p53 mutations were strongly associated with the deletion of 17p and the unmutated IgVH locus (both P < .001). Survival assessed from the time of abnormality detection was significantly reduced in patients with both missense (P < .001) and nonmissense p53 mutations (P = .004). In addition, patients harboring missense mutation located in p53 DNA-binding motifs (DBMs), structurally well-defined parts of the DNA-binding domain, manifested a clearly shorter median survival (12 months) compared with patients having missense mutations outside DBMs (41 months; P = .002) or nonmissense alterations (36 months; P = .005). The difference in survival was similar in the analysis limited to patients harboring mutation accompanied by del(17p) and was also confirmed in a subgroup harboring TP53 defect at diagnosis. The patients with p53 DBMs mutation (at diagnosis) also manifested a short median time to first therapy (TTFT; 1 month).
The substantially worse survival and the short TTFT suggest a strong mutated p53 gain-of-function phenotype in patients with CLL with DBMs mutations. The impact of p53 DBMs mutations on prognosis and response to therapy should be analyzed in investigative clinical trials.
TP53 缺陷与慢性淋巴细胞白血病（CLL）的不良预后之间存在明显的关联。目前尚不清楚是否携带 TP53 突变的患者代表了一个同质的预后组。
我们通过 p53 酵母功能测定和互补间期荧光原位杂交分析，评估了本机构从 2003 年至 2010 年间确定的携带 CLL 和 p53 缺陷的患者的生存情况，该分析检测了 del(17p)。
在 550 例患者中发现 100 例存在 TP53 基因缺陷。p53 突变与 17p 缺失和未突变的 IgVH 基因座密切相关（均 P <.001）。从异常检测时开始评估的生存情况，错义突变（P <.001）和非错义 p53 突变的患者（P =.004）明显降低。此外，携带位于 p53 DNA 结合基序（DBM）内的错义突变的患者的中位生存期明显缩短（12 个月），而位于 DBM 之外的错义突变患者（41 个月；P =.002）或非错义改变患者（36 个月；P =.005）。在仅限于携带突变伴 del(17p)的患者的分析中，生存差异相似，在诊断时存在 TP53 缺陷的亚组中也得到了证实。p53 DBM 突变（在诊断时）的患者也表现出较短的首次治疗中位时间（TTFT；1 个月）。
较差的生存和较短的 TTFT 提示，在具有 DBM 突变的 CLL 患者中，存在强烈的突变 p53 获得性功能表型。应在临床试验中分析 p53 DBM 突变对预后和治疗反应的影响。
