Analysis of VHL Gene Alterations and their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma.
Analysis of VHL Gene Alterations and their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma.
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DOI：
10.1158/1078-0432.ccr-09-2131
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发表时间：
2009-12-15
期刊：
影响因子：
--
通讯作者：
Banks RE
中科院分区：
文献类型：
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作者：
Young AC;Craven RA;Cohen D;Taylor C;Booth C;Harnden P;Cairns DA;Astuti D;Gregory W;Maher ER;Knowles MA;Joyce A;Selby PJ;Banks RE
对常规（透明细胞）肾细胞癌（RCC）患者VHL基因的遗传和表观遗传变化进行综合分析，并确定其与临床病理特征和预后的相关性。通过突变检测、杂合性缺失（LOH）和启动子甲基化分析确定86例常规rcc的VHL状态，将原始队列扩展到177例患者。对数据进行分析，探讨VHL变化、临床参数和预后之间的潜在关系。在可评估的肿瘤中，LOH占89.2%，突变占74.6%，甲基化占31.3%；86.0%的样本发现双等位基因失活（LOH和突变或甲基化），而只有3.4%的样本未发现VHL。一些关联被认为包括LOH和分级、结节状态和坏死、突变和性别以及甲基化和分级之间的关联。与无VHL患者相比，双等位基因失活可能与更好的总生存率相关，尽管后一组的小样本数严重限制了这一分析，需要独立证实。本研究报告了常规RCC伴VHL变化的最高比例之一，并提示VHL状态与临床变量之间可能存在关系。这些数据表明，VHL缺陷可能定义了传统的rcc，但特异性VHL改变的临床意义只能通过在蛋白质水平上确定其生物学效应来阐明，而不是通过单独的遗传或表观遗传分析。
To carry out a comprehensive analysis of genetic and epigenetic changes of the von Hippel Lindau (VHL) gene in patients with conventional (clear cell) renal cell carcinoma (RCC) and to determine their significance relative to clinicopathological characteristics and outcome. The VHL status in 86 conventional RCCs was determined by mutation detection, loss of heterozygosity (LOH) and promoter methylation analysis, extending our original cohort to a total of 177 patients. Data was analysed to investigate potential relationships between VHL changes, clinical parameters and outcome. LOH was found in 89.2%, mutation in 74.6% and methylation in 31.3% of evaluable tumours; evidence of biallelic inactivation (LOH and mutation or methylation alone) was found in 86.0% whilst no involvement of VHL was found in only 3.4% of samples. Several associations were suggested including between LOH and grade, nodal status and necrosis, between mutation and sex and between methylation and grade. Biallelic inactivation may be associated with better overall survival compared to patients with no VHL involvement although small sample numbers in the latter group severely limit this analysis which requires independent confirmation. This study reports one of the highest proportions of conventional RCC with VHL changes, and suggests possible relationships between VHL status and clinical variables. The data suggests that VHL defects may define conventional RCCs but the clinical significance of specific VHL alterations will only be clarified by the determination of their biological effect at the protein level rather than through genetic or epigenetic analysis alone.