Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel-Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors
Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel-Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors
复制标题
von Hippel-Lindau 病的家族内表型异质性和端粒异常：对个性化监测计划和 VHL 相关肿瘤发病机制的影响
DOI：
10.3389/fgene.2019.00358
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发表时间：
2019-04-24
影响因子：
3.7
通讯作者：
Gong, Kan
中科院分区：
文献类型：
--
作者：
Wang, Jiangyi;Peng, Xiang;Gong, Kan
von Hippel-Lindau（VHL）病是一种遗传性癌症综合征，生存率低。目前的建议对所有患者提出了统一的监测策略，忽略了明显的表型变化。在这项研究中，我们的目的是确认VHL疾病的表型异质性和潜在的机制。共有151对亲子对被纳入遗传预测分析，77对同胞对被纳入出生顺序效应分析。采用4种统计方法比较不同世代、不同胎次患者的发病年龄。结果表明，儿童平均发病年龄比父母早18.9岁，四种统计方法均有统计学意义。母亲患病的第一胎兄弟姐妹比其他兄弟姐妹晚发病8.3年。端粒缩短被证实与VHL家系的遗传预期有关，但未能解释胎次效应。此外，父母和子女之间（p = 0.834）以及第一个出生的患者和其他兄弟姐妹之间（p = 0.390）的总生存率没有显著差异。本研究提供了VHL家系内表型异质性的确切证据和可能机制，有助于更新监测指南。
von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intrafamilial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.