Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients.
Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients.
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中国冯希佩尔-林道病患者基因型-表型相关性
DOI：
10.18632/oncotarget.16594
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发表时间：
2017-06-13
期刊：
影响因子：
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通讯作者：
Gong K
中科院分区：
文献类型：
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作者：
Peng S;Shepard MJ;Wang J;Li T;Ning X;Cai L;Zhuang Z;Gong K
von Hippel-Lindau（VHL）病是由VHL基因突变引起的，并表现出显着的表型变异性。中国VHL患者的基因型-表型相关性尚不清楚。为了建立中国VHL患者基因型与表型的相关性，我们收集了来自115个无关家族的291例VHL患者的VHL突变和表型。采用Kaplan-Meier曲线和考克斯回归模型分析突变类型水平、突变区域水平和突变密码子水平的基因型-表型相关性。我们发现错义突变增加了嗜铬细胞瘤发生的风险，但降低了中枢神经系统成血管细胞瘤（CHB）和胰腺病变的风险。VHL缺失的患者更容易发生视网膜血管瘤。肾细胞癌中无义突变、移码突变或剪接位点突变更常见。外显子2的突变比其他外显子的突变具有更高的风险和更早的诊断年龄（HR = 1.684，95% CI 1.082-2.620，p = 0.021; 27.0 ± 9.7岁vs 32.8 ± 11.7岁，p = 0.024），而外显子3突变的患者更容易发生嗜铬细胞瘤（HR = 2.760，95% CI 1.419-5.370，p = 0.003）。密码子80或密码子167的突变比其他突变具有显著更高的嗜铬细胞瘤风险（HR = 4.678，95%CI 1.392-15.724，p = 0.013; HR = 4.683，95%CI 2.515-8.719，p < 0.001）。因此，VHL突变类型、突变区域和突变密码子可作为VHL疾病的表型预测因子。突变区域和突变密码子可能有助于VHL患者的定向监视和监测。
von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082–2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419–5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392–15.724, p = 0.013; HR = 4.683, 95% CI 2.515–8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.