Molecular subclassification of kidney tumors and the discovery of new diagnostic markers
Molecular subclassification of kidney tumors and the discovery of new diagnostic markers
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DOI：
10.1038/sj.onc.1206869
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发表时间：
2003-10-02
期刊：
影响因子：
8
通讯作者：
Teh, BT
中科院分区：
文献类型：
--
作者：
Takahashi, M;Yang, XMJ;Teh, BT
我们分析了70个不同组织亚型的肾脏肿瘤的表达谱，以确定这些亚组是否可以通过它们的基因表达谱来区分，并深入了解每个亚型背后的分子机制。共收集39例肾透明细胞癌、7例原发和1例转移性乳头状肾细胞癌、6例颗粒型肾细胞癌、5例嫌色肾细胞癌、5例肉瘤样肾细胞癌、2例嗜酸细胞瘤、3例肾盆移行细胞癌和5例肾母细胞瘤组织。基于3560个选定的cDNA的全局基因聚类，我们在透明细胞、乳头状细胞、嫌色RCC/嗜酸细胞瘤、TCC和Wilms亚型中发现了明显的分子特征。这些亚型中的每个亚型的紧密聚集表明它们的组织学特征所反映的不同的肿瘤发生途径。在肾透明细胞癌分组中，出现了与临床结果相关的两个亚组，证实了基因表达特征作为生存预测因子的潜在用途。在所谓的颗粒细胞RCC(不再首选的亚型的术语)中，六种情况都没有聚集在一起，支持当前的观点，即它们不代表单一实体。对四例“颗粒状RCC”的盲目组织学重新评估导致它们被重新分配到其他现有的组织学亚型，每个亚型都与我们的分子分类相一致。最后，我们找到了每个亚型特有的基因集合。为了确定其中一些基因作为新的亚型标记的用途，我们选择了4个基因，并对40例原发性肾肿瘤进行了免疫组织化学分析。结果与基因表达芯片数据一致：谷胱甘肽S转移酶α在透明细胞肾癌中高表达，甲酰消旋酶在乳头状肾癌中高表达，碳酸氢酶II在嫌色肾癌中高表达，K19在膀胱移行细胞癌中高表达。总之，我们证明了肾癌的分子图谱与其组织学亚型密切相关。我们还在这些亚型中发现了可能具有重要诊断和治疗意义的差异表达基因。
We analysed the expression profiles of 70 kidney tumors of different histological subtypes to determine if these subgroups can be distinguished by their gene expression profiles, and to gain insights into the molecular mechanisms underlying each subtype. In all, 39 clear cell renal cell carcinomas (RCC), seven primary and one metastatic papillary RCC, six granular RCC from old classification, five chromophobe RCC, five sarcomatoid RCC, two oncocytomas, three transitional cell carcinomas (TCC) of the renal pelvis and five Wilms' tumors were compared with noncancerous kidney tissues using microarrays containing 19 968 cDNAs. Based on global gene clustering of 3560 selected cDNAs, we found distinct molecular signatures in clear cell, papillary, chromophobe RCC/ oncocytoma, TCC and Wilms' subtypes. The close clustering in each of these subtypes points to different tumorigenic pathways as reflected by their histological characteristics. In the clear cell RCC clustering, two subgroups emerged that correlated with clinical outcomes, confirming the potential use of gene expression signatures as a predictor of survival. In the so-called granular cell RCC ( terminology for a subtype that is no longer preferred), none of the six cases clusters together, supporting the current view that they do not represent a single entity. Blinded histological re-evaluation of four cases of 'granular RCC' led to their reassignment to other existing histological subtypes, each compatible with our molecular classification. Finally, we found gene sets specific to each subtype. In order to establish the use of some of these genes as novel subtype markers, we selected four genes and performed immunohistochemical analysis on 40 cases of primary kidney tumors. The results were consistent with the gene expression microarray data: glutathione S-transferase alpha was highly expressed in clear cell RCC, a methylacyl racemase in papillary RCC, carbonic anhydrase II in chromophobe RCC and K19 in TCC. In conclusion, we demonstrated that molecular profiles of kidney cancers closely correlated with their histological subtypes. We have also identified in these subtypes differentially expressed genes that could have important diagnostic and therapeutic implications.