Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer
Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer
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DOI：
10.1038/sj.onc.1207878
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发表时间：
2004-11-04
期刊：
影响因子：
8
通讯作者：
Bartek, J
中科院分区：
文献类型：
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作者：
Bartkova, J;Guldberg, P;Bartek, J
检查点激酶2 （Chk2）是基因组完整性检查点中的肿瘤抑制因子和信号换能器，在DNA损伤反应中协调细胞周期进程与DNA修复或细胞死亡。Chk2缺陷发生在各种散发性恶性肿瘤的亚群中，并易患几种类型的遗传性癌。然而，Chk2在膀胱肿瘤中的地位尚不清楚。在这里，我们报告了58例晚期（T2 - T4级）人类膀胱癌，免疫组织化学分析显示6例（10.3%）患者肿瘤特异性减少或缺乏Chk2蛋白。后一个亚群的遗传分析表明，Chk2阴性癌# 668在一个Chk2等位基因中含有截断突变1100delC，而对应的第二个等位基因缺失。在该患者的种系中也发现了1100delC突变。肿瘤# 668的TP53测序鉴定出两个错义突变。此外，在没有任何dna损伤治疗的情况下，绝大多数肿瘤在Chk2的Thr68上表现出“计划外的”活化磷酸化。我们的研究结果表明，在侵袭性膀胱癌中，原本处于休眠状态的DNA损伤信号传感器Chk2被异常激活，并且这种可能的促凋亡检查点信号可以通过这些肿瘤亚群中Chk2和/或p53肿瘤抑制因子的失活而被禁用。
Checkpoint kinase 2 (Chk2) is a tumour suppressor and signal transducer in genome integrity checkpoints that coordinate cell-cycle progression with DNA repair or cell death in response to DNA damage. Defects of Chk2 occur in subsets of diverse sporadic malignancies and predispose to several types of hereditary carcinomas. However, the status of Chk2 in tumours of the urinary bladder remains unknown. Here, we report that among 58 advanced ( grade T2 - T4) human bladder carcinomas, immunohistochemical analysis revealed tumour-specific reduction or lack of Chk2 protein in 6 ( 10.3%) cases. Genetic analysis of the latter subset showed that a Chk2-negative carcinoma # 668 harboured a truncating mutation 1100delC, in one Chk2 allele and loss of the corresponding second allele. The 1100delC mutation was also found in the germ line of this patient. Sequencing of TP53 in tumour # 668 identified two missense mutations. Furthermore, the vast majority of the tumours showed 'unscheduled' activatory phosphorylation on Thr68 of Chk2 in the absence of any DNA-damaging treatment. Our results indicate that the otherwise dormant DNA damage signal transducer Chk2 is aberrantly and constitutively activated in invasive urinary bladder carcinomas, and that such likely proapoptotic checkpoint signalling can be disabled by inactivation of Chk2 and/or p53 tumour suppressors in subsets of these tumours.