Genotype-phenotype correlations in von Hippel-Lindau disease
Genotype-phenotype correlations in von Hippel-Lindau disease
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DOI：
10.1002/humu.20385
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发表时间：
2007-02-01
期刊：
影响因子：
3.9
通讯作者：
Maher, Eamorm R.
中科院分区：
文献类型：
--
作者：
Ong, Kai Ren;Woodward, Emma R.;Maher, Eamorm R.
von Hippel,Lindau （VHL）病是一种由VHL肿瘤抑制基因突变引起的显性遗传性家族性癌症综合征。VHL疾病表现出明显的表达变异，嗜铬细胞瘤的存在与错义VHL突变有关。我们分析了573例VHL患者的基因型-表型相关性。VHL患者和高危亲属的常规临床和放射学监测与视网膜血管瘤病的检出率增加（73%对59%的病例）和肾细胞癌（RCC）诊断年龄的降低（44.0 +/- 10.9对39.7 +/- 10.3岁）相关。我们证实了嗜铬细胞瘤与先前描述的错义突变之间的关联，但将错义突变分为导致表面氨基酸替换的突变和破坏结构完整性的突变，表明表面氨基酸替换会导致更高的嗜铬细胞瘤风险。无义突变或移码突变个体的视网膜血管瘤和RCC的年龄相关风险明显高于破坏VHL基因产物（pVHL）结构完整性的缺失或错义突变个体（P = 0.022和P = 0.0008）。这些结果扩展了VHL疾病中基因型-表型-蛋白质结构的相关性，并为未来VHL疾病的化学预防研究提供了基础。
von Hippel,Lindau (VHL) disease is a dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene. VHL disease displays marked variation in expression and the presence of pheochromocytoma has been linked to missense VHL mutations. We analyzed genotype-phenotype correlations in 573 individuals with VHL disease. Routine clinical and radiological surveillance of VHL patients and at-risk relatives was associated with increased detection of retinal angiomatosis (73 vs. 59% of cases) and a reduction in age at diagnosis of renal cell carcinoma (RCC) (44.0 +/- 10.9 vs. 39.7 +/- 10.3 years). We confirmed the association of pheochromocytoma with missense mutations described previously, but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk. Age at first manifestation of VHL disease was significantly earlier (P = 0.001), and age-related risks of retinal angiomas and RCC were higher (P = 0.022 and P = 0.0008, respectively) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product (pVHL). These results extend genotype-phenotype-protein structure correlations in VHL disease and provide a baseline for future chemoprevention studies in VHL disease.