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Peer-reviewedCC BY-NC-NDJournal of cancer research and clinical oncology

Hotspot mutations and tumour spectrum in von Hippel-Lindau syndrome: genotype-phenotype analysis of a large Chinese cohort.

  • Chuandong Wang1,2,3,4
  • Jianhui Qiu1,2,3,4
  • Tao Liu1,2,3,4
  • Yuhang Bao1,2,3,4
  • Jingcheng Zhou5,6,7,8
  • Yizhou Wang9
  • Kan Gong10,11,12,13
13 affiliations
  1. 1Department of Urology, Peking University First Hospital, Beijing, 100034, China.
  2. 2Institute of Urology, Peking University, Beijing, 100034, China.
  3. 3Beijing Key Laboratory of Precision Medicine and Innovative Translation for Urogenital Diseases, Beijing, 100034, China.
  4. 4National Urological Cancer Center, Beijing, 100034, China.
  5. 5Department of Urology, Peking University First Hospital, Beijing, 100034, China. [email protected].
  6. 6Institute of Urology, Peking University, Beijing, 100034, China. [email protected].
  7. 7Beijing Key Laboratory of Precision Medicine and Innovative Translation for Urogenital Diseases, Beijing, 100034, China. [email protected].
  8. 8National Urological Cancer Center, Beijing, 100034, China. [email protected].
  9. 9Department of Central Laboratory, Peking University First Hospital, Beijing, China. [email protected].
  10. 10Department of Urology, Peking University First Hospital, Beijing, 100034, China. [email protected].
  11. 11Institute of Urology, Peking University, Beijing, 100034, China. [email protected].
  12. 12Beijing Key Laboratory of Precision Medicine and Innovative Translation for Urogenital Diseases, Beijing, 100034, China. [email protected].
  13. 13National Urological Cancer Center, Beijing, 100034, China. [email protected].
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Abstract

Background

Von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant multisystem tumour syndrome caused by germline VHL mutations. The traditional classification of VHL syndrome, which is largely based on pheochromocytoma penetrance, is insufficient for individualised surveillance and management. This study aimed to improve mutation-specific risk stratification and define genotype-phenotype correlations of recurrent hotspot mutations in a large Chinese cohort.Methods

This retrospective single-centre study included 674 patients with VHL disease from 283 unrelated families. Four recurrent hotspot mutation subtypes were analysed: codon 65 missense mutations, exon 2 deletion, c.481C > T, and c.224_226del. Kaplan-Meier analysis and univariate and multivariate Cox regression models were used to assess age-related tumour risks and survival outcomes.Results

Codon 65 missense mutations were associated with a lower risk of retinal angioma and pheochromocytoma, indicating a relatively mild phenotype. Exon 2 deletion was characterised by a higher prevalence, earlier onset, and increased age-related risk of retinal angioma and worse renal cell carcinoma (RCC)-specific survival. Increased prevalences and age-related risks of central nervous system hemangioblastoma (CHB), RCC, and pancreatic cysts or tumours were associated with c.481C > T mutations. The c.224_226del subtype showed a distinct CHB-predominant phenotype, with higher CHB incidence, earlier onset, lower pancreatic lesion risk, and higher overall mortality.Conclusion

Recurrent hotspot VHL mutation subtypes were associated with distinct clinical phenotypes and prognostic patterns. Mutation subtype-based classification (covering 19.6% of patients with VHL syndrome) may provide more precise guidance for surveillance, clinical decision-making, and genetic counselling than traditional broad classification models.

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Cite

BibTeXRIS
BibTeX
@article{wang2026hotspot,
  title = {{Hotspot mutations and tumour spectrum in von Hippel-Lindau syndrome: genotype-phenotype analysis of a large Chinese cohort.}},
  author = {Chuandong Wang and Jianhui Qiu and Tao Liu and Yuhang Bao and Jingcheng Zhou and Yizhou Wang and Kan Gong},
  journal = {Journal of cancer research and clinical oncology},
  year = {2026},
  month = aug,
  doi = {10.1007/s00432-026-06564-z},
  url = {https://europepmc.org/article/MED/42967954},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Hotspot mutations and tumour spectrum in von Hippel-Lindau syndrome: genotype-phenotype analysis of a large Chinese cohort.
AU  - Chuandong Wang
AU  - Jianhui Qiu
AU  - Tao Liu
AU  - Yuhang Bao
AU  - Jingcheng Zhou
AU  - Yizhou Wang
AU  - Kan Gong
PY  - 2026
DA  - 2026/08/04
JO  - Journal of cancer research and clinical oncology
DO  - 10.1007/s00432-026-06564-z
UR  - https://europepmc.org/article/MED/42967954
AB  - Background  Von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant multisystem tumour syndrome caused by germline VHL mutations. The traditional classification of VHL syndrome, which is largely based on pheochromocytoma penetrance, is insufficient for individualised surveillance and management. This study aimed to improve mutation-specific risk stratification and define genotype-phenotype correlations of recurrent hotspot mutations in a large Chinese cohort.Methods  This retrospective single-centre study included 674 patients with VHL disease from 283 unrelated families. Four recurrent hotspot mutation subtypes were analysed: codon 65 missense mutations, exon 2 deletion, c.481C > T, and c.224_226del. Kaplan-Meier analysis and univariate and multivariate Cox regression models were used to assess age-related tumour risks and survival outcomes.Results  Codon 65 missense mutations were associated with a lower risk of retinal angioma and pheochromocytoma, indicating a relatively mild phenotype. Exon 2 deletion was characterised by a higher prevalence, earlier onset, and increased age-related risk of retinal angioma and worse renal cell carcinoma (RCC)-specific survival. Increased prevalences and age-related risks of central nervous system hemangioblastoma (CHB), RCC, and pancreatic cysts or tumours were associated with c.481C > T mutations. The c.224_226del subtype showed a distinct CHB-predominant phenotype, with higher CHB incidence, earlier onset, lower pancreatic lesion risk, and higher overall mortality.Conclusion  Recurrent hotspot VHL mutation subtypes were associated with distinct clinical phenotypes and prognostic patterns. Mutation subtype-based classification (covering 19.6% of patients with VHL syndrome) may provide more precise guidance for surveillance, clinical decision-making, and genetic counselling than traditional broad classification models.
SN  - 0171-5216
SN  - 1432-1335
ER  -