Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets.
Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets.
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DOI：
10.1158/0008-5472.can-11-1698
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发表时间：
2012-01-01
期刊：
影响因子：
11.2
通讯作者：
Nathanson KL
中科院分区：
文献类型：
--
作者：
Dondeti VR;Wubbenhorst B;Lal P;Gordan JD;D'Andrea K;Attiyeh EF;Simon MC;Nathanson KL
散发性透明细胞肾细胞癌 (ccRCC) 是最常见的成人肾癌类型，通常与 3p 和 5q 染色体上的基因组拷贝数畸变有关。 3p 染色体畸变与肿瘤抑制基因 von-Hippel Lindau (VHL) 失活有关，该基因会激活缺氧诱导因子 HIF1α 和 HIF2α。相比之下，染色体 5q 上的 ccRCC 基因仍有待定义。在这项研究中，我们对 54 个散发性 ccRCC 肿瘤的高密度拷贝数和基因表达数据进行了综合分析，确定了分泌糖蛋白 STC2（斯钙素 2）和蛋白聚糖 VCAN（versican）作为 ccRCC 中潜在的 5q 癌基因。在功能测定中，STC2 和 VCAN 均通过抑制细胞死亡来促进肿瘤发生。使用相同的方法，我们还研究了 ccRCC 的两种 VHL 缺陷亚型，它们同时表达 HIF1α 和 HIF2α (H1H2) 或仅表达 HIF2α (H2)。该分析揭示了每组基因组畸变的独特模式，平均而言，H1H2 组比 H2 组显示出更多的异常基因组。我们的发现共同提供了两种具有不同特征的亚型以及两种潜在的染色体 5q 癌基因的分子定义，为理解 ccRCC 提供了重大进展，其过度表达足以通过限制细胞死亡来促进肿瘤发生。
Sporadic clear cell Renal Cell Carcinoma (ccRCC), the most common type of adult kidney cancer, is often associated with genomic copy number aberrations on chromosomes 3p and 5q. Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), which activates the hypoxia inducible factors HIF1α and HIF2α. In contrast, ccRCC genes on chromosome 5q remain to be defined. In this study, we performed an integrated analysis of high-density copy number and gene expression data for 54 sporadic ccRCC tumors that identified the secreted glycoprotein STC2 (stanniocalcin 2) and the proteoglycan VCAN (versican) as potential 5q oncogenes in ccRCC. In functional assays, STC2 and VCAN each promoted tumorigenesis by inhibiting cell death. Using the same approach, we also investigated the two VHL-deficient subtypes of ccRCC, which express both HIF1α and HIF2α (H1H2) or only HIF2α (H2). This analysis revealed a distinct pattern of genomic aberrations in each group, with the H1H2 group displaying, on average, a more aberrant genome than the H2 group. Together our findings provide a significant advance in understanding ccRCC by offering a molecular definition of two subtypes with distinct characteristics as well as two potential chromosome 5q oncogenes, the overexpression of which is sufficient to promote tumorigenesis by limiting cell death.