High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer
High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer
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DOI：
10.1016/s0002-9440(10)64592-0
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发表时间：
2000-09-01
影响因子：
6
通讯作者：
Sauter, G
中科院分区：
文献类型：
--
作者：
Richter, J;Wagner, U;Sauter, G
通过比较基因组杂交的研究显示，19 q13染色体区域在膀胱癌中频繁扩增。细胞周期蛋白E基因（CCNE）编码细胞周期蛋白依赖性激酶2的调节亚基，已被定位于19 q13。为了研究细胞周期蛋白E改变在膀胱癌中的作用，构建了来自1，842名膀胱癌患者的2，317份标本的组织微阵列，并通过荧光原位杂交分析CCNE扩增和通过免疫组织化学分析细胞周期蛋白E蛋白过表达。荧光原位杂交分析显示，在1,561例可评估的肿瘤中，仅30例（1.9%）出现扩增，扩增与分期和分级显著相关（均P < 0.0005）。在1,873例可解释的肿瘤中，免疫组化检测的细胞周期蛋白E表达在233例（12.4%）中为强表达，在354例（18.9%）中为弱表达，在1,286例中为阴性表达。大多数（62.1%）CCNE扩增的肿瘤呈强免疫化学阳性（P < 0.0001）。蛋白表达频率从pTa（22.2%）到pT 1（45.5%; P < 0.0001）增加，但随后在pT 2 -4期下降（29.4%; pT 1与pT 2 -4相比P < 0.0001）。在所有患者中，细胞周期蛋白E低表达与总生存率低相关（P < 0.0001），但与分期无关，对预后无影响。结论是细胞周期蛋白E过表达是膀胱癌亚群的特征，特别是在早期浸润阶段。在> 1，500个阵列膀胱癌中CCNE基因扩增和蛋白表达的预后影响的分析在2周内完成，说明了组织微阵列技术如何显著地促进了癌症中分子改变的临床相关性的评估。
Studies by comparative genomic hybridization revealed that the 19q13 chromosomal region is frequently amplified in bladder cancer. The cyclin E gene (CCNE), coding for a regulatory subunit of cyclin-dependent kinase 2, has been mapped to 19q13. To investigate the role of cyclin E alterations in bladder cancer, a tissue microarray of 2,317 specimens from 1,842 bladder cancer patients was constructed and analyzed for CCNE amplification by fluorescence in situ hybridization and for cyclin-E protein overexpression by immunohistochemistry. Fluorescence in situ hybridization analysis showed amplification in only 30 of the 1,561 evaluable tumors (1.9%), Amplification was significantly associated with stage and grade (P < 0.0005 each). Immunohistochemically detectable cyclin E expression was strong in 233 (12.4%), weak in 354 (18.9%), and negative in 1,286 of the 1,873 interpretable tumors. The majority (62.1%) of CCNE-amplified tumors were strongly immunohistochemistry-positive (P < 0.0001), The frequency of protein expression increased from stage pTa (22.2%) to pT1 (45.5%; P < 0.0001) but then decreased for stage pT2-4 (29.4%; P < 0.0001 for pT1 versus pT2-4). Low cyclin E expression was associated with poor overall survival in all patients (P < 0.0001), but had no prognostic impact independent of stage. It is concluded that cyclin E overexpression is characteristic to a subset of bladder carcinomas, especially at the stage of early invasion, This analysis of the prognostic impact of CCNE gene amplification and protein expression in >1,500 arrayed bladder cancers was accomplished in a period of 2 weeks, illustrating how the tissue microarray technology remarkably facilitates the evaluation of the clinical relevance of molecular alterations in cancer.