Bladder cancer stage and outcome by array-based comparative genomic hybridization
Bladder cancer stage and outcome by array-based comparative genomic hybridization
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DOI：
10.1158/1078-0432.ccr-05-0177
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发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Waldman, FM
中科院分区：
文献类型：
--
作者：
Blaveri, E;Brewer, JL;Waldman, FM
目的：膀胱癌的发生被认为遵循由遗传改变的积累驱动的疾病进展的替代途径。本研究的目的是评估基因组，不稳定性和膀胱癌临床phenotype.Experimental设计的措施之间的关联：全基因组拷贝数配置文件获得了98个不同阶段（29 pT（a），14 pT（1），55 pT（2-4））和等级（21个低级别和8个高级别的浅表肿瘤）的基于阵列的比较基因组杂交（CGH）。每个阵列包含2，464个细菌人工染色体和P1克隆，整个基因组的平均分辨率为1.5 Mb。共有54例肌肉浸润病例有随访信息。对具有“好”（存活> 2年）与“坏”（死亡< 2年）预后的肌肉浸润性肿瘤患者进行总体结果分析。结果：阵列CGH分析显示拷贝数改变和基因组不稳定性随着阶段和结果的增加而显著增加。基因组改变的比例（FGA）在不同阶段的肿瘤之间存在显著差异（pT（a）与pT（1），P = 0.0003; pTa与pT（2-4），P = 0.02;以及pT（1）与pT（2-4），P = 0.03）。在调整多重比较后，鉴定不同肿瘤阶段之间显著不同的个体克隆（假发现率< 0.05）。对于肌层浸润性肿瘤，FGA与患者预后相关（预后不良与预后良好患者，P = 0.002），并基于多变量考克斯比例风险法被确定为总体预后的唯一独立预测因子。无监督层次聚类分离“好。“和“差”预后肌肉浸润性肿瘤成簇，显示与FGA和生存率显著相关（Kaplan-Meier，P = 0.019）。监督肿瘤分类（预测分析微阵列）有71%的分类成功率的基础上，102个独特的clones.Conclusions：阵列为基础的CGH确定定量和定性差异的DNA。根据肿瘤分期和分级以高分辨率显示拷贝数改变。基因组改变与肌肉浸润性肿瘤的预后差相关，与其他临床病理参数无关。基因组不稳定性的测量增加了膀胱肿瘤预后预测的独立能力。
Purpose: Bladder carcinogenesis is believed to follow alternative pathways of disease progression driven by an accumulation of genetic alterations. The purpose of this study was to evaluate associations between measures of genomic, instability and bladder cancer clinical phenotype.Experimental Design: Genome-wide copy number profiles were-obtained for 98 bladder tumors of diverse stages (29 pT(a), 14 pT(1), 55 pT(2-4)) and grades (21 low-grade and 8 high-grade superficial tumors) by array-based comparative genomic hybridization (CGH). Each array contained 2,464 bacterial artificial chromosome and P1 clones, providing an average resolution of 1.5 Mb across the genome. A total of 54 muscle-invasive cases had follow-up information available. Overall outcome analysis was done-for patients with,muscle-invasive tumors having ''good" (alive > 2 years) versus "bad" (dead in < 2 years) prognosis.Results: Array CGH analysis showed significant increases in copy number alterations and genomic instability with increasing stage and with outcome. The fraction of genome altered (FGA) was significantly different between tumors of different stages (pT(a) versus pT(1), P = 0.0003; pTa versus pT(2-4), P = 0.02; and pT(1) versus pT(2-4), P = 0.03). Individual clones that differed significantly between different tumor stages were identified after adjustment for multiple comparisons (false discovery rate < 0.05). For muscle-invasive tumors, the FGA was associated with patient outcome (bad versus good prognosis patients, P = 0.002) and was identified as the only independent predictor of overall outcome based on a multivariate Cox proportional hazards method. Unsupervised hierarchical clustering separated "good." and "bad" prognosis muscle-invasive tumors into clusters that showed significant association with FGA and survival (Kaplan-Meier, P = 0.019). Supervised tumor classification (prediction analysis for microarrays) had a 71% classification success rate based on 102 unique clones.Conclusions: Array-based CGH identified quantitative and qualitative differences in DNA. copy number alterations at high resolution according to tumor stage and grade. Fraction genome altered was associated with worse outcome in muscle-invasive tumors, independent of other clinicopathologic parameters. Measures of genomic instability add independent power to outcome prediction of bladder tumors.