The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population.
The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population.
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基于突变位置的 Von Hipple Lindau 病基因型-表型关联：中国人群 577 例病例的回顾性研究。
DOI：
10.3389/fgene.2020.532588
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发表时间：
2020
影响因子：
3.7
通讯作者：
Gong K
中科院分区：
文献类型：
--
作者：
Qiu J;Zhang K;Ma K;Zhou J;Gong Y;Cai L;Gong K
Von Hippel-Lindau(VHL)病是一种遗传性肾癌综合征，患者更容易受到肾细胞癌(RCC)、胰腺囊肿或肿瘤(PCT)、中枢神经系统血管母细胞瘤(CHB)、视网膜血管瘤(RA)和嗜铬细胞瘤(PHEO)的影响。位于3p25的VHL基因突变可能会损害VHL蛋白的功能，从而导致疾病的发生。目前尚不清楚为什么VHL患者存在明显的表型差异。在这里，我们的目的是确定突变类型和位置是否影响表型。我们从211个家系中招募了577名中国VHL患者，并根据突变类型和位置将他们分为三组和六个亚组。用Cox生存分析和Kaplan-Meier分析比较组间年龄相关肿瘤风险。无义突变或移码突变位于VHL蛋白第117位之前的患者(NoF1亚组)发生VHL相关肿瘤(HR=0.638，95%CI 0.461~0.883，p=0.007)、慢性乙型肝炎(HR=0.596，95%CI 0.409~0.868，p=0.007)或PCT(HR=0.595，95%CI 0.368~0.961，p=0.034)的风险低于突变在117位之后的患者(NoF2亚组)。与合并NOF2亚组和其他截短突变患者相比，NoF1亚组患者发生慢性乙型肝炎(HR=0.652，95%CI 0.476~0.893，p=0.008)和心绞痛(HR=0.605，95%CI 0.398~0.918，p=0.018)的年龄相关风险仍较低。相应地，NoF1亚组的估计中位寿命(对55岁，p=0.037)长于NoF2亚组。在VHL错义突变患者中，仅有一小部分患者(2 86例错义突变携带者中的2 3例)携带既不涉及HIF-α结合区也不涉及细长蛋白C结合区的突变，这些突变属于MO亚组。Mo亚组似乎具有较高的年龄相关性PHEO风险。在整个队列中，Pheo是CHB(p=0.001)和生存(p=0.005)的独立保护因素。RA和CHB未能预测彼此的年龄相关风险。VHL基因的突变类型和位置与表型有关。遗传咨询师可以基于更详细的基因-表型相关性更准确地预测表型。进一步的基因型-表型研究应侧重于肿瘤复发、进展和转移的预测。基因型-表型相关的深层次分子机制值得进一步探讨。
Von Hippel-Lindau (VHL) disease is a hereditary kidney cancer syndrome, with which patients are more likely to get affected by renal cell carcinoma (RCC), pancreatic cyst or tumor (PCT), central nervous system hemangioblastoma (CHB), retinal angiomas (RA), and pheochromocytoma (PHEO). Mutations of VHL gene located in 3p25 may impair the function of the VHL protein and lead to the disease. It’s unclear why obvious phenotype varieties exist among VHL patients. Here we aimed to ascertain whether the mutation types and locations affect the phenotype. We enrolled 577 Chinese VHL patients from 211 families and divided them into three groups and six subgroups according to their mutation types and locations. Cox survival analysis and Kaplan-Meier analysis were used to compare intergroup age-related tumor risks. Patients with nonsense or frameshift mutations that were located before residues 117 of VHL protein (NoF1 subgroup) hold lower age-related risks of VHL associated tumors (HR = 0.638, 95%CI 0.461–0.883, p = 0.007), CHB (HR = 0.596, 95%CI 0.409–0.868, p = 0.007) or PCT (HR = 0.595, 95%CI 0.368–0.961, p = 0.034) than patients whose mutations were located after residues 117 (NoF2 subgroup). Patients in NoF1 subgroup still had lower age-related risks of CHB (HR = 0.652, 95%CI 0.476–0.893, p = 0.008) and PCT (HR = 0.605, 95%CI 0.398–0.918, p = 0.018) compared with those in combined NoF2 subgroup and other truncating mutation patients. NoF1 subgroup correspondingly had a longer estimated median lifespan (64 vs. 55 year, p = 0.037) than NoF2 subgroup. Among patients with missense mutations of VHL, only a small minority (23 of 286 missense mutations carriers) carried mutations involving neither HIF-α binding region nor elongin C binding region, who were grouped in MO subgroup. MO subgroup seemed to have a higher age-related risk of PHEO. In the whole cohort (n = 577), PHEO was an independent protective factor for CHB (p = 0.001) and survival (p = 0.005). RA and CHB failed to predict the age-related risk of each other. The mutation types and locations of VHL gene are associated with phenotypes. Genetic counselors could predict phenotypes more accurately based on more detailed genotype-phenotype correlations. Further genotype-phenotype studies should focus on the prediction of tumor recurrence, progression, and metastasis. The deep molecular mechanism of genotype-phenotype correlation is worth further exploring.
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