Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors.
Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors.
复制标题
DOI：
10.1158/1078-0432.ccr-07-4921
复制
发表时间：
2008-08-01
影响因子：
11.5
通讯作者：
Moore, Lee E.
中科院分区：
文献类型：
--
作者：
Nickerson, Michael L.;Jaeger, Erich;Shi, Yangu;Durocher, Jeffrey A.;Mahurkar, Sunil;Zaridze, David;Matveev, Vsevolod;Janout, Vladimir;Kollarova, Hellena;Bencko, Vladimir;Navratilova, Marie;Szeszenia-Dabrowska, Neonilia;Mates, Dana;Mukeria, Anush;Holcatova, Ivana;Schmidt, Laura S.;Toro, Jorge R.;Karami, Sara;Hung, Rayjean;Gerard, Gary F.;Linehan, W. Marston;Merino, Maria;Zbar, Berton;Boffetta, Paolo;Brennan, Paul;Rothman, Nathaniel;Chow, Wong-Ho;Waldman, Frederic M.;Moore, Lee E.
提供对透明细胞肾癌（ccRCC）特有的癌症基因组中von Hippel-Lindau VHL基因的体细胞突变和启动子超甲基化的全面、彻底分析。确定VHL基因变异和变异亚型与患者和肿瘤特征之间的关系。作为在中欧进行的一项大型肾癌病例对照研究的一部分，我们分析了205例经组织学证实的患者肿瘤活检标本中的VHL突变和启动子甲基化，采用了灵敏的高通量方法（核酸内切酶扫描和桑格测序），并分析了VHL启动子中的11个CpG位点。我们在82.4%的病例中发现了突变，这是迄今为止报道的最高VHL基因突变患病率。11个VHL启动子CpG位点的分析显示，8.3%的肿瘤是高甲基化，所有突变阴性。总的来说，91%的ccRCC通过遗传或表观遗传机制表现出基因改变。对患者和肿瘤特征的分析显示，某些突变亚型与Fuhrman核分级、转移、淋巴结阳性和自我报告的RCC家族史显着相关。使用这些准确、灵敏和实用的方法检测VHL基因改变提供了证据，证明绝大多数组织学证实的ccRCC肿瘤具有VHL基因的遗传或表观遗传改变，并支持VHL改变是ccRCC致癌作用的早期事件的假设。这些发现还表明，VHL分子亚型可以为病因学、预后和转化研究提供组织学相似的ccRCC病例中肿瘤异质性的敏感标志物。
To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau VHL gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well characterized, histologically-confirmed patient tumor biopsies utilizing a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing), and analysis of 11CpG sites in the VHL promoter. We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Detection of VHL gene alterations using these accurate, sensitive and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.