Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney.
Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney.
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DOI：
10.1158/0008-5472.can-09-0146
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Signoretti S
中科院分区：
文献类型：
--
作者：
Beroukhim R;Brunet JP;Di Napoli A;Mertz KD;Seeley A;Pires MM;Linhart D;Worrell RA;Moch H;Rubin MA;Sellers WR;Meyerson M;Linehan WM;Kaelin WG Jr;Signoretti S
最近对VHL肿瘤抑制基因在遗传性和散发性肾透明细胞癌（ccRCC）中的作用的认识，为转移性ccRCC患者带来了新的治疗方法，尽管几乎所有患者最终都死于这种疾病。我们对90种肿瘤（包括散发性和VHL疾病相关肿瘤）的拷贝数变化和基因表达谱进行了综合的全基因组分析，希望找到ccRCC的新治疗靶点。我们确定了14个非随机拷贝数变化区域，包括7个扩增区域（1q，2q，5q，7q，8q，12p和20q）和7个缺失区域（1p，3p，4q，6q，8p，9p和14q）。一项旨在鉴定相关基因的分析显示，VHL是3p缺失峰中的3个基因之一，CDKN 2A和CDKN 2B是9p缺失峰中的唯一基因，MYC是8q扩增峰中的唯一基因。对扩增样品中扩增峰中一致过表达的基因进行了综合分析，证实MYC是8q扩增的潜在靶点，并在其他区域鉴定了候选癌基因。基因组图谱的比较显示，VHL疾病相关肿瘤与散发性肿瘤的亚组相似，因此总体上更同质。没有双等位基因VHL失活证据的散发性肿瘤分为2组：一组基因组谱与大多数ccRCC高度不相似，第二组基因组谱与VHL双等位基因失活的肿瘤更相似。
Recent insights into the role of the VHL tumor suppressor gene in hereditary and sporadic clear cell carcinoma of the kidney (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of 3 genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors, and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into 2 groups: one group with genomic profiles highly dissimilar to the majority of ccRCC, and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL.