Detection of DNA copy number changes and oncogenic signaling abnormalities from gene expression data reveals MYC activation in high-grade papillary renal cell carcinoma
Detection of DNA copy number changes and oncogenic signaling abnormalities from gene expression data reveals MYC activation in high-grade papillary renal cell carcinoma
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DOI：
10.1158/0008-5472.can-06-4571
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Teh, Bin Tean
中科院分区：
文献类型：
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作者：
Furge, Kyle A.;Chen, Jindong;Teh, Bin Tean
乳头状肾细胞癌（RCC）占成人肾肿瘤的10%至15%;然而，与散发性乳头状RCC的发展和进展相关的分子遗传事件在很大程度上仍不清楚。根据组织学、细胞遗传学和基因表达差异，乳头状RCC可分为两种亚型。I型肿瘤（类似于60-70%）通常是低等级的，具有良好的结果，而2型肿瘤（类似于30-40%）与增加的细胞遗传学复杂性、高肿瘤等级和不良预后相关。在这项研究中，来自乳头状肾细胞癌的基因表达数据的计算分析显示，MYC通路激活的转录签名指示存在于高级别2型乳头状肾细胞癌。MYC标签与染色体8 q的扩增和映射到染色体8 q24的MYC的过表达相关。MYC激活的重要性在2型乳头状肾细胞癌细胞系模型中通过药理学和短干扰RNA介导的活性Myc信号传导抑制得到证实。这些结果提供了计算和遗传证据，Myc的激活与乳头状2型RCC的侵袭性相关。因此，考虑抑制MYC信号通路的组分作为高级别乳头状肾细胞癌治疗干预的途径将是有用的。
Papillary renal cell carcinoma (RCC) represents 10% to 15% of adult renal neoplasms; however, the molecular genetic events that are associated with the development and progression of sporadic papillary RCC remain largely unclear. Papillary RCCs can be divided into two subtypes based on histologic, cytogenetic, and gene expression differences. Type I tumors (similar to 60-70%) are generally low grade with favorable outcome,,whereas type 2 tumors (similar to 30-40%) are associated with increased cytogenetic complexity, high tumor grade, and poor prognosis. In this study, computational analysis of gene expression data derived from papillary RCC revealed that a transcriptional signature indicative of MYC pathway activation is present in high-grade type 2 papillary RCC. The MYC signature is associated with amplification of chromosome 8q and overexpression of MYC that maps to chromosome 8q24. The importance of MYC activation was confirmed by both pharmacologic and short interfering RNA-mediated inhibition of active Myc signaling in a cell line model of type 2 papillary RCC. These results provide both computational and genetic evidence that activation of Myc is associated with the aggressiveness of papillary type 2 RCC. Therefore, it will be useful to consider inhibition of components of the MYC signaling pathway as avenues for therapeutic intervention in high-grade papillary RCC.