An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: Evidence for modifier effects
An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: Evidence for modifier effects
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DOI：
10.1086/302037
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发表时间：
1998-10-01
影响因子：
9.8
通讯作者：
Maher, ER
中科院分区：
文献类型：
--
作者：
Webster, AR;Richards, FM;Maher, ER
von Hippel-Lindau病（VHL）是一种显性遗传的家族性癌症综合征，易患眼和CNS血管母细胞瘤、肾细胞癌（RCC）和嗜铬细胞瘤。家族间和家族内表达的变异性都是公认的。嗜铬细胞瘤易感性的家族间差异归因于等位基因异质性，例如特定的错义生殖系突变赋予这种并发症的高风险。然而，在大多数情况下，肿瘤易感性似乎不受潜在VHL突变类型的影响。为了探讨表型变异的原因，我们检查了183例具有生殖系VHL基因突变的个体，以确定眼部肿瘤的存在和数量。眼部血管瘤病的患病率并没有随着年龄的增长而增加，并且这些肿瘤在基因携带者中的分布与预期的随机分布有显著差异。眼部血管母细胞瘤患者小脑血管母细胞瘤和RCC的发病率显著增加（风险比分别为2.3和4.0）。眼部肿瘤的数量在1/2度亲缘关系的个体中显着相关，但在更远的亲缘关系的个体中不相关。这些研究结果表明，VHL眼部肿瘤的发展是在早期确定的，并受到遗传和/或环境修饰剂作用于多个部位的影响。谷胱甘肽-S-转移酶M1基因（GSTM 1）或细胞色素P450 2D 6基因（CYP 2D 6）的功能多态性与眼部或肾脏受累的严重程度无显著相关性。
von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing to ocular and CNS hemangioblastomas, renal-cell carcinoma (RCC), and pheochromocytoma. Both interfamilial and intrafamilial variability in expression is well recognized. Interfamilial differences in pheochromocytoma susceptibility have been attributed to allelic heterogeneity such that specific missense germ-line mutations confer a high risk for this complication. However, in most cases, tumor susceptibility does not appear to be influenced by the type of underlying VHL mutation. To probe the causes of phenotypic variation, we examined 183 individuals with germ-line VHL gene mutations, for the presence and number of ocular tumors. The prevalence of ocular angiomatosis did not increase with age, and the distribution of these tumors in gene carriers was significantly different than the expected stochastic distributions. Individuals with ocular hemangioblastomas had a significantly increased incidence of cerebellar hemangioblastoma and RCC (hazard ratios 2.3 and 4.0, respectively). The number of ocular tumors was significantly correlated in individuals of 1/2 degree relatedness but not in more distantly related individuals. These findings suggest that the development of VHL ocular tumors is determined at an early age and is influenced by genetic and/or environmental modifier effects that act at multiple sites. Functional polymorphisms in the glutathione-S-transferase M1 gene (GSTM1) or the cytochrome P450 2D6 gene (CYP2D6) did not show a significant association with the severity of ocular or renal involvement.