Genotype and p'henotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein
Genotype and p'henotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein
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基于 VHL 蛋白中 HIF-α 结合位点改变的 von Hippel-Lindau 病基因型和表型相关性
DOI：
10.1038/gim.2017.261
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发表时间：
2018-10-01
影响因子：
8.8
通讯作者：
Gong, Kan
中科院分区：
文献类型：
--
作者：
Liu, Sheng-Jie;Wang, Jiang-Yi;Gong, Kan
目的：Von Hippel-Lindau（VHL）病是一种罕见的遗传性癌症综合征，可缩短预期寿命。我们的目的是构建一个更有价值的基因型-表型相关性的基础上改变VHL蛋白（pVHL）。方法：VHL患者（n = 339）招募和分组的基础上突变类型：HIF-α结合位点错义（HM）突变，非HIF-α结合位点错义（nHM）突变，截短（TR）突变。VHL相关肿瘤和患者生存率的风险与VHL相关肿瘤和患者生存率进行了compared.Results：错义突变赋予嗜铬细胞瘤的风险增加（HR = 1.854，p = 0.047）相比，截短突变。HM组的嗜铬细胞瘤风险低于nHM组（HR = 0.298，p = 0.003），但HM组和TR组之间相似（HR = 0.901，p = 0.810）。nHM组患者发生嗜铬细胞瘤的风险较高（HR = 3.447，p < 0.001）和中枢神经系统血管母细胞瘤（CHB）风险较低（HR = 0.700，p = 0.045）、肾细胞癌（HR = 0.610，p = 0.024）和胰腺肿瘤（HR = 0.382，p < 0.001）中的那些。此外，nHM突变与更好的总生存率独立相关。（HR = 0.345，p = 0.005）和CHB特异性生存期（HR = 0.129，p = 0.005）。改良的基因型-表型相关性将VHL基因突变、底物结合位点和表型多样性联系起来（发病率和生存率），并提供更准确的信息，遗传咨询和发病机制的研究。
Purpose: Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).Methods: VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-alpha binding site missense (HM) mutations, non-HIF-alpha binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.Results: Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations.Conclusion: The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.