Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy
Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy
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DOI：
10.1016/s1470-2045(07)70002-5
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发表时间：
2007-02-01
期刊：
影响因子：
51.1
通讯作者：
Shariat, Shahrokh F.
中科院分区：
文献类型：
--
作者：
Karam, Jose A.;Lotan, Yair;Shariat, Shahrokh F.
背景细胞凋亡的去调控是人类致癌的一个特征。本研究旨在探讨膀胱癌根治术和双侧淋巴清扫术中细胞凋亡标记物Bcl2、caspase-3、P53和Survivin的表达及其与肿瘤预后的关系。方法对226例患者(中位随访36.9个月[IQR13.3~79.0])应用含核心的系列组织芯片进行Bcl2、Caspase-3、P53和Survivin的免疫组化染色。其中73例(32%)、111例(49%)、120例(53%)和141例(%)的Bcl2、Caspase-3、P53和Survivin的表达发生了改变。单因素分析显示，bc1-2、caspase-3、p53和Survivin的表达改变均与疾病复发的高风险相关(风险比2.24[95%可信区间1.51-3.32]，p<；0.001；1.73[1.16-2.59]，p=0.007；2.70[1.77-4.12]，p<；0.001；和2.32[1.48-3.63]，p<；0.001)和疾病死亡率(分别为2.06[1.333.18]，p=0.001；2.35[1.483.73]，p<；0.001；3.23[1.985.28]，p；0.001；和2.64[1.574.44]，p<；0.001)。随着改变的生物标志物数量的增加，复发风险和疾病特异性死亡逐渐增加。经多因素分析，四种标志物的改变与疾病复发率(4.031.23-13.16p=0.021)和疾病特异性死亡率(6.84[1.4332.63]，p=0.016)独立相关。在包含标准预测因子的模型中加入改变的标记物的数量显著提高了其对疾病复发和疾病特异性生存的预测准确性。解释bcl2、caspase-3、p53和Survivin对膀胱癌的进展具有协同作用。对接受根治性膀胱切除术的患者的联合细胞凋亡标志物状态和改变的标志物数量的评估提供了预后信息，有助于识别那些疾病复发和死亡的高危人群，他们可以从早期辅助治疗中受益。
Background Deregulation of apoptosis is a characteristic of human carcinogenesis. We aimed to investigate expression of the apoptosis markers Bcl-2, caspase-3, P53, and survivin and the association with oncological outcomes of patients treated by radical cystectomy and bilateral lymphadenectomy for urothelial-cell carcinoma of the bladder.Methods Bcl-2, caspase-3, P53, and survivin immunostaining was undertaken on serial tissue microarrays containing cores from 226 consecutive patients (median follow-up 36.9 months [IQR 13.3-79.0]). 200 bootstrap resamples with replacement were done to reduce overfit bias and for internal validation.Findings Expression of Bcl-2, caspase-3, P53, and survivin was altered in 73 (32%), 111 (49%), 120 (53%), and 141 (64%) patients, respectively. By univariate analysis, altered expression of Bcl-2, caspase-3, P53, and survivin were all associated with high probability of disease recurrence (hazard ratio 2.24 [95% CI 1.51-3.32], p < 0.001; 1.73 [1.16-2.59], p=0.007; 2.70 [1.77-4.12], p < 0.001; and 2.32 [1.48-3.63], p < 0.001) and disease-specific mortality (2.06 [1.33-3.18], p=0.001; 2.35 [1.48-3.73], p < 0.001; 3.23 [1.98-5.28], p < 0.001; and 2.64 [1.57-4.44], p < 0.001; respectively). Risk of recurrence and disease-specific mortality progressively grew with increasing number of altered biomarkers. By multivariate analysis, alteration of four markers was independently associated with high rates of disease recurrence (4.03 [1.23-13.16], p=0.021) and disease-specific mortality (6.84 [1.43-32.63], p=0.016). Addition of the number of altered markers to a model that included standard predictors significantly enhanced its predictive accuracy for disease recurrence and disease-specific survival.Interpretation Bcl-2, caspase-3, P53, and survivin have a cooperative effect on progression of bladder cancer. Assessment of combined apoptosis marker status and number of altered markers in patients treated by radical cystectomy provides prognostic information that could help to identify those at high risk for disease recurrence and mortality, who could benefit from early adjuvant treatment.