Research Papers:

Genotype-phenotype correlations in Chinese von Hippel–Lindau disease patients

Shuanghe Peng, Matthew J. Shepard, Jiangyi Wang, Teng Li, Xianghui Ning, Lin Cai, Zhengping Zhuang and Kan Gong _

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Oncotarget. 2017; 8:38456-38465. https://doi.org/10.18632/oncotarget.16594

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Shuanghe Peng1,2,3, Matthew J. Shepard4,5, Jiangyi Wang1,2,3, Teng Li1,2,3, Xianghui Ning1,2,3, Lin Cai1,2,3, Zhengping Zhuang5, Kan Gong1,2,3

1Department of Urology, Peking University First Hospital, Beijing, P.R China

2Institute of Urology, Peking University, Beijing, P.R China

3National Urological Cancer Center, Beijing, P.R China

4Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA

5Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

Correspondence to:

Kan Gong, email: gongkan_pku@126.com

Keywords: von Hippel–Lindau, VHL, genotype-phenotype correlation, VHL mutation, phenotypic predictor

Received: February 23, 2017     Accepted: March 17, 2017     Published: March 27, 2017


von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082–2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419–5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392–15.724, p = 0.013; HR = 4.683, 95% CI 2.515–8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.

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