Wild-type VHL Clear Cell Renal Cell Carcinomas Are a Distinct Clinical and Histologic Entity: A 10-Year Follow-up
Wild-type VHL Clear Cell Renal Cell Carcinomas Are a Distinct Clinical and Histologic Entity: A 10-Year Follow-up
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DOI：
10.1016/j.euf.2015.06.001
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发表时间：
2016-02-01
影响因子：
5.4
通讯作者：
Rioux-Leclercq, Nathalie
中科院分区：
文献类型：
--
作者：
Dagher, Julien;Kammerer-Jacquet, Solene-Florence;Rioux-Leclercq, Nathalie
背景：肾透明细胞癌（ccRCC）是一种侵袭性肿瘤，在初次诊断或随访时转移风险为50%。肿瘤抑制基因von Hippel-Lindau（VHL）的失活存在于>70%的散发性病例中，其失活机制有三种：基因座缺失、基因突变或启动子高甲基化。目的：将VHL基因的完整状态与临床和病理标准相关联。我们回顾性纳入了2002年至2005年期间接受手术的98例ccRCC患者。VHL基因缺失（71/98; 72.4%），突变（68/98; 69.4%），启动子高甲基化分别通过基因拷贝分析、基因测序和甲基化特异性多重连接依赖性探针扩增筛选98例中的13例（13.3%）。使用卡方和Student t检验分析VHL亚组与研究标准之间的关系。生存率用对数秩检验和Kaplan-Meier曲线进行分析。与发生两起事件的ccRCC相比（66.3%），肿瘤没有或有一个遗传事件（33.6%）与较高的核IV级相关（p = 0.02），转移（p = 0.04），肉瘤样成分（p = 0.01），致密淋巴细胞浸润（p = 0.013）和血管内皮生长因子过度表达（> 30%）（p = 0.003），这也是多变量分析后的独立因素。此外，野生型VHL肿瘤（无失活事件，11.2%）与淋巴结受累相关（p = 0.019），与具有1个或2个VHL失活事件的ccRCC患者（107个月; p = 0.016）相比，患有这种类型肿瘤的患者的特异性生存期为33个月。回顾性研究设计中野生型肿瘤的数量较少，这是本研究的局限性。（10年的临床随访）证实了具有野生型VHL的ccRCC是需要正式鉴定的高度侵袭性肿瘤。在活化的VHL肿瘤中，野生型亚组定义了具有较差存活率的侵袭性表型，这表明这些肿瘤必须进行更彻底的筛查。(C)2015年欧洲泌尿外科协会。Elsevier B. V.出版，保留所有权利。
Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with 50% risk of metastases at initial diagnosis or at follow-up. An inactivation of the tumor-suppressor gene von Hippel-Lindau (VHL) is present in >70% of sporadic cases by two of three different mechanisms: locus deletion, gene mutation, or promoter hypermethylation.Objective: To correlate the complete status of the VHL gene with clinical and pathologic criteria.Design, setting, and participants: We retrospectively included 98 patients with ccRCC who underwent surgery between 2002 and 2005. VHL gene deletions (71 of 98; 72.4%), mutations (68 of 98; 69.4%), and promoter hypermethylations (13 of 98; 13.3%) were screened by gene copy analysis, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification, respectively.Outcome measurements and statistical analysis: Relationships between VHL subgroups and the studied criteria were analyzed using chi-square and Student t tests. Survival was analyzed with the log-rank test and Kaplan-Meier curves.Results and limitations: Compared with ccRCCs with two events (66.3%), tumors with no or one genetic event (33.6%) were associated with a higher nuclear grade IV (p = 0.02), metastases (p = 0.04), sarcomatoid component (p = 0.01), dense lymphocyte infiltrate (p = 0.013), and vascular endothelial growth factor overexpression (> 30%) (p = 0.003), which was also an independent factor after multivariate analysis. Furthermore, wild-type VHL tumors (no inactivating event, 11.2%) were associated with nodal involvement (p = 0.019), and patients with this type of tumor had a specific survival of 33 mo compared with patients with ccRCCs having one or two VHL inactivating events (107 mo; p = 0.016). The retrospective design with small number of wild-type tumors was a limitation of this work.Conclusions: This long-term study (10-yr clinical follow-up) confirms that ccRCCs with wild-type VHL are highly aggressive tumors that need to be formally identified.Patient summary: Among activated VHL tumors, the wild-type subgroup defines an aggressive phenotype with worse survival rates, suggesting that these tumors must be more thoroughly screened. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.