Thornton Patrick D, Gruszka-Westwood Alicja M, Hamoudi Rifat A, Atkinson Shayne, Kaczmarek Pawel, Morilla Ricardo M, Hilditch Benjamin L, A'Hern Roger, Matutes Estella, Catovsky Daniel
Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust and Institute of Cancer Research, London, UK.
Hematol J. 2004;5(1):47-54. doi: 10.1038/sj.thj.6200325.
Abnormalities of TP53 in chronic lymphocytic leukaemia (CLL) correlate with aggressive disease and transformation. We studied 115 patients with CLL including 90 untreated, 25 with heavily pretreated/refractory CLL using fluorescent in situ hybridisation (FISH) to detect allelic loss at chromosome 17p and flow cytometry (FC) to test p53 protein overexpression. A total of 17 cases were identified with TP53 deletion and/or protein expression. Both tests correlated in 10 of 17 patients; in six, one or the other abnormality was detected and in one case, with a deletion, flow cytometry failed. Material for direct DNA sequencing was available in 14 of 17 cases. Mutations were found in seven cases. Five of 14 patients with allelic loss and seven of 13 expressing p53 protein had a mutation. These were single-base substitutions and were located in exons 5, 7 or 8. Mutations were not found in 13 of 14 other cases without deletions by FISH or protein expression. The incidence of p53 abnormalities in this series was 15%, with a significant difference between untreated patients (7%) and the pretreated/refractory group (50%; P<0.01). Abnormal p53 was predicted for shorter survival, regardless of the method used. We confirm that p53 abnormalities are more common in refractory CLL and that mutations occur at the known hot spots. Testing for TP53 deletions by FISH and protein expression by FC is an effective and simple way of screening patients who are likely to have aggressive disease. DNA sequencing adds little to these methods in identifying the population at risk.
慢性淋巴细胞白血病（CLL）中TP53的异常与侵袭性疾病及转化相关。我们研究了115例CLL患者，其中90例未经治疗，25例为经过大量预处理/难治性CLL患者，采用荧光原位杂交（FISH）检测17号染色体短臂的等位基因缺失，并通过流式细胞术（FC）检测p53蛋白过表达。共鉴定出17例存在TP53缺失和/或蛋白表达异常的病例。在17例患者中有10例两种检测结果相关；6例仅检测到一种异常，1例存在缺失，但流式细胞术检测失败。17例中有14例可获得用于直接DNA测序的样本。发现7例存在突变。14例等位基因缺失患者中有5例以及13例表达p53蛋白的患者中有7例存在突变。这些均为单碱基替换，位于外显子5、7或8。14例其他病例中，FISH检测无缺失且无蛋白表达异常，其中13例未发现突变。该系列中p53异常的发生率为15%，未经治疗的患者（7%）与预处理/难治性组（50%；P<0.01）之间存在显著差异。无论采用何种方法，p53异常均预示着生存期较短。我们证实p53异常在难治性CLL中更为常见，且突变发生在已知的热点区域。通过FISH检测TP53缺失以及通过FC检测蛋白表达是筛查可能患有侵袭性疾病患者的有效且简便的方法。在识别高危人群方面，DNA测序对这些方法的补充作用不大。
