The Academic Department of Urology of La Pitié-Salpétrière and of Tenon, Groupe Hospitalo-Universitaire Est, Assistance-Publique Hôpitaux de Paris Faculté , Paris, France.
BJU Int. 2012 Jun;109(12):1864-70. doi: 10.1111/j.1464-410X.2011.10661.x. Epub 2011 Oct 28.
What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti-angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. • A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. • RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. • Alteration of the product of the Von Hippel-Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. • However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. • Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. • Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. • Recent technological developments, such as large-scale analysis and high-speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.
散发性透明细胞肾细胞癌（ccRCC）在多达 90%的病例中由位于染色体 3p 上的 VHL 基因突变引起。
该基因在缺氧反应中起关键作用，包括刺激新血管生成。
自 2006 年以来，针对该途径的抗血管生成治疗已用于转移性患者，客观缓解率高达 45%。
然而，这些治疗方法并不能直接针对肿瘤细胞，因此尽管进行了治疗，仍有可能导致疾病进展。
最近的大规模分析表明，ccRCC 存在大量遗传异质性。
相关的改变包括在 15%的病例中涉及甲基化调节的基因，这表明表观遗传修饰的重要性，以及在 41%的病例中染色质重塑复合物 PRMB1 的截断突变。
对这些肿瘤进行系统筛查是全面确定 RCC 体细胞遗传结构的一种方法，以改善肿瘤分类，开发预后和预测标志物，并针对参与癌变的新分子途径。
本研究的目的是什么？它增加了什么新的知识？
本文通过强调我们目前对致癌基因途径的理解及其当前和未来的临床应用，对应用于肾细胞癌（RCC）的肿瘤遗传学的最新进展进行了批判性回顾。
RCC 是转化研究的一个模型，因为对分子途径的深入了解导致了几种转移性 RCC 患者的靶向治疗选择。
血管内皮生长因子通路中 Von Hippel-Lindau 基因/缺氧诱导因子的改变在致癌作用中得到了很好的描述，是目前转移性 RCC 治疗的靶点。
然而，这种癌症存在大量遗传异质性，目前的治疗方法并不能直接针对肿瘤细胞。
提高总体生存率仍然是一个具有挑战性的目标，但目前缺乏治疗反应的预后和预测生物标志物。
从肿瘤分类、预后标志物和治疗反应预测指标以及暴露于危险因素时发生 RCC 的个体易感性的基因组方法中，还需要进一步的信息。
最近的技术发展，如大规模分析和高速测序，将允许对肿瘤进行系统筛查，以全面确定 RCC 的体细胞遗传结构。
