Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer
Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer
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DOI：
10.1158/0008-5472.can-05-3074
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Selby, PJ
中科院分区：
文献类型：
--
作者：
Banks, RE;Tirukonda, P;Selby, PJ
von Hippel-Lindau（VHL）肿瘤抑制基因的遗传和表观遗传变化在散发性传统肾细胞癌（cRCC）中很常见。对这些变化的临床意义的进一步了解可能会增加对不同病理学或可能受益于特定靶向治疗的患者亚组的生物学理解和识别。我们全面检查了115例接受肾切除术患者组织样本中的VHL状态，其中包括96例散发性cRCC。在cRCC患者中，78.4%的样本中发现杂合性缺失，71%的样本中发现突变，20.4%的样本中发现启动子甲基化。多重连接依赖的探针扩增确定了几个样品中的基因内拷贝数的变化，其中包括两个，否则被认为是VHL无关。总体而言，在74.2%的cRCC患者中发现了双等位基因失活的证据。许多突变是新的，大约三分之二是潜在的截短。对这些和其他已发表的研究结果的检查证实了影响密码子117和164的突变热点，并揭示了密码子60至78中的共同突变区域。甲基化和突变的性别特异性差异，虽然没有达到统计学意义（P = 0.068和0.11），甲基化和多态性之间可能存在关联。VHL亚组之间在临床病理特征（包括分期、分级、肿瘤大小、无癌生存期和总生存期）方面无显著差异，但杂合性缺失与分级之间存在显著相关性，尽管基于突变位置的生存差异可能趋势明显。
Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation-dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHL-noninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent.