Renal Cell Carcinoma in von Hippel-Lindau Disease-From Tumor Genetics to Novel Therapeutic Strategies.
Renal Cell Carcinoma in von Hippel-Lindau Disease-From Tumor Genetics to Novel Therapeutic Strategies.
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DOI：
10.3389/fped.2018.00016
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发表时间：
2018
影响因子：
2.6
通讯作者：
Zschiedrich S
中科院分区：
文献类型：
--
作者：
Kim E;Zschiedrich S
von Hippel-Lindau（VHL）病是由VHL肿瘤抑制基因突变引起的常染色体显性遗传综合征，导致许多缺氧诱导的基因失调。受影响的个体发生复发性和双侧肾囊肿和发育不良病变的风险增加，这些病变可能进展为透明细胞肾细胞癌（ccRCC）。在上皮细胞VHL基因失活后，ccRCC通过额外的遗传改变进化，导致肿瘤内和肿瘤间异质性。基因组学研究已经确定了参与表观遗传调控和磷酸肌醇3-激酶-AKT-雷帕霉素（mTOR）通路激活的机制靶点的基因中的频繁突变。目前，局部治疗选择包括保留肾单位手术和替代消融手术。对于晚期转移性疾病，可进行全身治疗，包括抑制血管内皮生长因子途径和mTOR途径，以及免疫治疗。目前正在研究针对多种信号通路和/或增强免疫应答的多模式治疗。新的临床前模型将加速对ccRCC发展和进展的基础生物学的更深入了解，以及新型靶向治疗的开发，这将极大地为寻找用于诊断，预后和治疗反应的临床生物标志物提供信息。
von Hippel–Lindau (VHL) disease is an autosomal dominant syndrome caused by mutations in the VHL tumor-suppressor gene, leading to the dysregulation of many hypoxia-induced genes. Affected individuals are at increased risk of developing recurrent and bilateral kidney cysts and dysplastic lesions which may progress to clear cell renal cell carcinoma (ccRCC). Following the eponymous VHL gene inactivation, ccRCCs evolve through additional genetic alterations, resulting in both intratumor and intertumor heterogeneity. Genomic studies have identified frequent mutations in genes involved in epigenetic regulation and phosphoinositide 3-kinase–AKT–mechanistic target of rapamycin (mTOR) pathway activation. Currently, local therapeutic options include nephron-sparing surgery and alternative ablative procedures. For advanced metastatic disease, systemic treatment, including inhibition of vascular endothelial growth factor pathways and mTOR pathways, as well as immunotherapy are available. Multimodal therapy, targeting multiple signaling pathways and/or enhancing the immune response, is currently being investigated. A deeper understanding of the fundamental biology of ccRCC development and progression, as well as the development of novel and targeted therapies will be accelerated by new preclinical models, which will greatly inform the search for clinical biomarkers for diagnosis, prognosis, and response to treatment.
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DOI：
10.1056/nejmoa1510016
发表时间：
2015-11-05
期刊：
The New England journal of medicine
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Lonser, Russell R
影响因子：
6.6
作者：
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通讯作者：
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影响因子：
64.8
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DOI：
10.1200/jco.2016.70.7398
发表时间：
2017-02-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
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通讯作者：
Morris MJ