Lubensky I A, Gnarra J R, Bertheau P, Walther M M, Linehan W M, Zhuang Z
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA.
Am J Pathol. 1996 Dec;149(6):2089-94.
Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal lesions including cysts and renal cell carcinomas (RCCs). VHL gene deletions have been previously reported in VHL-associated macroscopic RCC. Although histological analysis suggests that microscopic cystic lesions in the VHL patients may represent precursors of the RCC, there is at present no direct molecular evidence of their relationship. To investigate the relationship between cystic lesions and RCC, 26 microdissected archival renal lesions from two VHL disease patients were studied for loss of heterozygosity at the VHL gene locus using polymerase chain reaction single-strand conformation polymorphism analysis. The renal lesions included 2 benign cysts, 5 atypical cysts, 5 microscopic RCCs in situ, 5 cysts lined by a single layer of cells, in which RCCs in situ were developing, and 2 microscopic and 7 macroscopic RCCs. Except for a single benign cyst, 25 of 26 renal lesions showed nonrandom allelic loss of the VHL gene. In either of the 2 patients, the same VHL allele was deleted in all of the lesions tested, indicating loss of the wild-type allele and retention of the inherited, mutated VHL allele. The results suggest that all clear-cell lesions in the VHL kidney represent neoplasms and that the loss of the VHL gene occurs early in their development. Atypical and benign cysts most likely represent the initial phenotype in malignant transformation to the RCC.
患有冯·希佩尔-林道（VHL）病的患者会出现一系列双侧透明细胞肾病变，包括囊肿和肾细胞癌（RCC）。先前已有报道VHL相关的肉眼可见的RCC中存在VHL基因缺失。尽管组织学分析表明VHL病患者的微小囊性病变可能是RCC的前体，但目前尚无它们之间关系的直接分子证据。为了研究囊性病变与RCC之间的关系，利用聚合酶链反应单链构象多态性分析，对两名VHL病患者的26个经显微切割的存档肾病变进行了VHL基因位点杂合性缺失研究。肾病变包括2个良性囊肿、5个非典型囊肿、5个原位微小RCC、5个由单层细胞衬里且有原位RCC正在形成的囊肿，以及2个微小RCC和7个肉眼可见的RCC。除了一个单一的良性囊肿外，26个肾病变中有25个显示VHL基因的非随机等位基因缺失。在这两名患者中的任何一名中，所有检测的病变中均缺失相同的VHL等位基因，表明野生型等位基因缺失而保留了遗传的、突变的VHL等位基因。结果表明，VHL肾中的所有透明细胞病变均代表肿瘤，且VHL基因缺失在其发展早期就已发生。非典型囊肿和良性囊肿很可能代表了向RCC恶性转化的初始表型。
