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Original research
Novel genetic characterisation and phenotype correlation in von Hippel-Lindau (VHL) disease based on the Elongin C binding site: a large retrospective study
  1. Haibiao Xie1,2,3,
  2. Kaifang Ma1,2,3,
  3. Jiufeng Zhang1,2,
  4. Baoan Hong2,
  5. Jingcheng Zhou2,
  6. Lei Li3,
  7. Kenan Zhang3,
  8. Kan Gong1,2,3,
  9. Lin Cai1,2,3
  1. 1 Department of Urology, Peking University First Hospital, Beijing, Beijing, China
  2. 2 Institute of Urology, Peking University, Beijing, China
  3. 3 Natiional Urological Cancer Center, Beijing, China
  1. Correspondence to Dr Lin Cai, Department of Urology, Peking University First Hospital; Institute of Urology, Peking University; National Urological Cancer Center, Beijing 100034, China; drcailin{at}


Background Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumour syndrome resulting from mutations in the VHL gene lineage, and its prognosis is generally poor. This study aimed to provide a more valuable genotype–phenotype correlation based on the Elongin C binding site in VHL disease.

Methods This study included 553 patients (194 families) who were diagnosed with VHL disease in our centre from September 2010 to February 2019. According to the type of gene mutation, the patients were divided into the Elongin C binding site missense mutation (EM) group, the non-Elongin C binding site missense mutation (nEM) group and the truncation mutation (TR) group. We analysed and compared the age-related tumour risk and prognosis of the three groups.

Results A total of 14 new intragenic mutations were found in this cohort. The age-related risk of central nervous system haemangioblastoma (CHB) and pancreatic tumour in the EM group was lower than in the combined nEM-TR group, while the corresponding risk of pheochromocytoma (PHEO) was higher. Additionally, the prognoses of EM and nEM-TR were analysed. The median survival period in the EM group was longer than that in the nEM-TR group, and both the total survival and the CHB-specific survival of the EM group were better than those of the nEM-TR group.

Conclusion In conclusion, our study demonstrated that the EM was an independent risk factor for PHEO. The EM is also an independent protective factor for CHB age-related risk, overall survival and CHB-specific survival in VHL disease. This modified genotype–phenotype correlation integrates gene mutation, the Elongin B binding site, and phenotypic diversity and provides a reference for clinical diagnosis.

  • genotype-phenotype
  • elongin c binding site
  • VHL syndrome
  • survival
  • tumor risk factors

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  • HX and KM contributed equally.

  • Contributors XHB, MKF, ZKN, LL and HBA collected the detailed information of patients with VHL. XHB and MKF analysed the clinical data. XHB and ZJF drafted the manuscript, ZJC and CL provided clinical expertise. GK and CL designed and supervised the project, established the workflow of the analysis. All authors have read and agreed to the final version of the manuscript.

  • Funding This study was funded by the National Natural Science Foundation of China (No. 81572506 and 81872081), and the Fundamental Research Funds for the Central Universities (No. BMU2018JI002).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The project was approved by the Medical Ethics Committee of Peking University First Hospital (Beijing, China). Informed consent was acquired from the subjects after understanding of the process and possible consequences of the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.