Gene Expression Profiling Reveals a New Classification of Adrenocortical Tumors and Identifies Molecular Predictors of Malignancy and Survival
Gene Expression Profiling Reveals a New Classification of Adrenocortical Tumors and Identifies Molecular Predictors of Malignancy and Survival
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DOI：
10.1200/jco.2008.18.5678
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发表时间：
2009-03-01
影响因子：
45.3
通讯作者：
Bertherat, Jerome
中科院分区：
文献类型：
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作者：
de Reynies, Aurelien;Assie, Guillaume;Bertherat, Jerome
目的肾上腺皮质肿瘤，尤其是恶性肿瘤，在诊断和预后评估方面仍具有挑战性。本文的目的是确定恶性肿瘤和survival.Patients和Methods 153单侧肾上腺皮质肿瘤的分子预测因子进行了研究微阵列（n = 92）或逆转录定量聚合酶链反应（n = 148）。使用无病生存期作为训练队列（n = 47）的终点，建立恶性肿瘤的双基因预测因子，然后在独立验证队列（n = 104）中进行验证。采用考克斯模型筛选出最佳候选基因，并采用对数秩检验验证最佳基因组合。同样，对于恶性肿瘤，一个两个基因的预测生存建立了一个训练队列（n = 23），然后在一个独立的验证队列（n = 35）进行测试，使用的总生存期为终点。ResultsUnsupervised聚类分析区分强大的恶性和良性肿瘤，并确定了两组恶性肿瘤有非常不同的结果。DLG 7和PINK 1的联合表达是无病生存期的最佳预测因子（对数秩P接近10（-12）），可以克服中间病理韦斯评分的不确定性，并且在调整韦斯评分后仍然显著（P < 1.3 x 10（-2））。在恶性肿瘤中，BUB 1B和PINK 1的联合表达是总生存率的最佳预测因子（P < 2 x 10（-6）），并且在校正MacFarlane分期后仍具有显著性（P <0.005）。恶性肿瘤和生存的分子预测因子是可靠的，除了病理和肿瘤分期之外，还提供了有价值的独立信息。这些原始工具应该为肾上腺肿瘤的管理提供重要的改进。J Clin Oncol 27：1108-1115. (C)2009年美国临床肿瘤学会
PurposeAdrenocortical tumors, especially cancers, remain challenging both for their diagnosis and prognosis assessment. The aim of this article is to identify molecular predictors of malignancy and of survival.Patients and MethodsOne hundred fifty-three unilateral adrenocortical tumors were studied by microarray (n = 92) or reverse transcription quantitative polymerase chain reaction (n = 148). A two-gene predictor of malignancy was built using the disease-free survival as the end point in a training cohort (n = 47), then validated in an independent validation cohort (n = 104). The best candidate genes were selected using Cox models, and the best gene combination was validated using the log-rank test. Similarly, for malignant tumors, a two-gene predictor of survival was built using the overall survival as the end point in a training cohort (n = 23), then tested in an independent validation cohort (n = 35).ResultsUnsupervised clustering analysis discriminated robustly the malignant and benign tumors, and identified two groups of malignant tumors with very different outcome. The combined expression of DLG7 and PINK1 was the best predictor of disease-free survival (log-rank P approximate to 10(-12)), could overcome the uncertainties of intermediate pathological Weiss scores, and remained significant after adjustment to the Weiss score (P < 1.3 x 10(-2)). Among the malignant tumors, the combined expression of BUB1B and PINK1 was the best predictor of overall survival (P < 2 x 10(-6)), and remained significant after adjusting for MacFarlane staging (P < .005).ConclusionGene expression analysis unravels two distinct groups of adrenocortical carcinomas. The molecular predictors of malignancy and of survival are reliable and provide valuable independent information in addition to pathology and tumor staging. These original tools should provide important improvements for adrenal tumors management. J Clin Oncol 27: 1108-1115. (C) 2009 by American Society of Clinical Oncology