Laboratoire de Génétique Oncologique EPHE, INSERM U743, Faculté de Médecine Paris-Sud, 94276 Le Kremlin-Bicêtre et Institut de cancérologie Gustave Roussy, 94800 Villejuif, France.
Semin Cancer Biol. 2013 Feb;23(1):26-37. doi: 10.1016/j.semcancer.2012.05.005. Epub 2012 May 30.
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome (1/36,000 live births) with highly penetrance that predispose to the development of a panel of highly vascularized tumors (model of tumoral angiogenesis). Main manifestations include central nervous system (CNS) and retinal haemangioblastomas, endolymphatic sac tumors, clear-cell renal cell carcinomas (RCC), phaeochromocytomas and pancreatic neuroendocrine tumors. RCC has become the first potential cause of mortality and VHL disease is the main cause of inherited RCC. The disease is caused by germline mutations in the VHL tumor-suppressor gene that plays a major role in regulation of the oxygen-sensing pathway by targeting the hypoxia-inducible factor HIF for degradation in proteasome. VHL has also major HIF-independent functions, specially in regulation of primary cilium, extracellular matrix and apoptosis. Somatic inactivation of the VHL gene is the main molecular event in most sporadic RCC and the treatment of advanced RCC has been revolutionized by targeted therapy with drugs that block angiogenesis. These drugs are now in first line in metastatic sporadic RCC and have shown promising results for RCC, pancreatic neuroendocrine tumors and malignant pheochromocytomas in VHL patients.
希佩尔-林道（VHL）病是一种罕见的常染色体显性遗传综合征（每 36000 例活产儿中有 1 例），具有高度外显率，易发生一系列高度血管化肿瘤（肿瘤血管生成模型）。主要表现包括中枢神经系统（CNS）和视网膜血管母细胞瘤、内淋巴囊肿瘤、透明细胞肾细胞癌（RCC）、嗜铬细胞瘤和胰腺神经内分泌肿瘤。RCC 已成为主要的死亡原因，VHL 病是遗传性 RCC 的主要原因。该疾病是由 VHL 肿瘤抑制基因的种系突变引起的，该基因在调节氧感应途径中起主要作用，通过靶向蛋白酶体降解缺氧诱导因子 HIF。VHL 还具有主要的 HIF 非依赖性功能，特别是在调节初级纤毛、细胞外基质和细胞凋亡方面。VHL 基因的体细胞失活是大多数散发性 RCC 的主要分子事件，针对血管生成的靶向治疗已彻底改变了晚期 RCC 的治疗。这些药物现已成为转移性散发性 RCC 的一线治疗药物，并在 VHL 患者的 RCC、胰腺神经内分泌肿瘤和恶性嗜铬细胞瘤中显示出良好的疗效。
