时间标签：数据日期 2026-11-05 · 生成时间 2026-11-05 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/11/02 – 2026/11/06 ｜ 情报发生日期 2026-11-05
研究问题
However, this classification approach may be limited by the overrepresentation of specific mutations (e.g., the mutation at amino acid 167) or the particularly distinct phenotypes associated with such mutations, which could influence the generalizability of genotype–phenotype analyses (Li et al. 2025).In this study, we aimed to identify detailed genotype–phenotype relationships of the main hotspot mutations based on mutation types, including codon 65 missense mutations (HIF-α binding site missense mutations), exon 2 deletion (truncation mutation, TR), c.481C > T (TR), and c.224_226del (TR).；Ultimately, we aimed to provide new VHL syndrome subtypes based on these hotspot mutations for improved monitoring and treatment.MethodsEthical considerationsThe present study was approved by the Ethics Committee of Peking University First Hospital (Beijing, China) (Ethics no.2026R0246).；Univariate and multivariate Cox proportional hazards regression models were used to determine whether sex, birth year, family history, and clinical type were independent risk factors for VHL-related manifestations and mortality.
方法
Patients present with multicentric and multiorgan tumours, including clear cell renal cell carcinoma (RCC), central nervous system hemangioblastoma (CHB), retinal angioma (RA), pheochromocytoma, and pancreatic cysts or tumours (PCT) (Liao et al. 2024; Ganner et al. 2025).；However, this traditional two-subtype classification method does not sufficiently describe all patients with VHL syndrome.；Furthermore, surveillance and individualised interventions are urgently required as over 90% of patients with pathogenic mutations exhibit VHL syndrome–related symptoms before the age of 65 (Peng et al. 2017).VHL encodes an E3 ubiquitin ligase with key regulatory functions.
核心结论
(2018) demonstrated that missense mutations located in the HIF-α binding region increased the risk of CHB while reducing the risk of pheochromocytoma.；These findings demonstrated that multiple recurrent VHL mutation subtypes were present in this cohort, which provided the basis for subsequent genotype–phenotype analyses (Table 1).Reduced risk of RA and pheochromocytoma in patients with codon 65 missense mutationsTo further investigate the clinicopathological characteristics associated with specific VHL mutations, missense mutations were classified into three subgroups for the primary analysis: codon 65 mutations, other missense mutations (oMMs), and truncation mutations (TRs) (Fig. 1).；We found that codon 65 mutations were associated with a lower age-related risk of RA and pheochromocytoma (both P < 0.001) than other missense mutations and truncation mutations (Fig. 2).
局限
However, this traditional two-subtype classification method does not sufficiently describe all patients with VHL syndrome.；However, VHL mutations impair its functions, leading to the stable presence of HIF-α and continuous activation of downstream angiogenesis, ultimately promoting the formation of malignant tumours (Buckley et al. 2024).Several studies have found significant associations between genotypes and phenotypes in patients with VHL syndrome (Binderup et al. 2016; Bangiyeva et al. 2009; Suzuki et al. 2024).；However, this classification approach may be limited by the overrepresentation of specific mutations (e.g., the mutation at amino acid 167) or the particularly distinct phenotypes associated with such mutations, which could influence the generalizability of genotype–phenotype analyses (Li et al. 2025).In this study, we aimed to identify detailed genotype–phenotype relationships of the main hotspot mutations based on mutation types, including codon 65 missense mutations (HIF-α binding site missense mutations), exon 2 deletion (truncation mutation, TR), c.481C > T (TR), and c.224_226del (TR).
对本项目的价值
中等价值：属「代谢 / 内分泌 / 肝肾老化」方向；代谢 / 内分泌 / 肝肾老化的界面栏目可用作本项目文献库与综述素材。 ｜ 价值分 2.6/5（★★★☆☆）
全文来源
PubMed PMC JATS（正文 36,868 字符，题名指纹 0.73，已过 PubMed PMCID 官方关联 + 题名指纹 + 正文长度归属校验）
原文题录
- 中文题名：von Hippel-Lindau 综合征的热点突变与肿瘤谱：中国大队列基因型-表型分析
- 英文标题：Hotspot mutations and tumour spectrum in von Hippel-Lindau syndrome: genotype-phenotype analysis of a large Chinese cohort.
- 期刊与标识：Journal of cancer research and clinical oncology · PMID 42967954 · DOI 10.1007/s00432-026-06564-z · PMC PMC13724643