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

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

doi:10.18632/oncotarget.16594

Abstract

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.

Highlights

Von Hippel–Lindau disease (VHL; OMIM Number 193300) is an autosomal-dominant inherited tumor predisposition syndrome
Patients with von Hippel–Lindau (VHL) are prone to the development of multiple neoplastic lesions including central nervous system hemangioblastomas (CHBs), retinal angiomas (RAs), renal cell carcinomas (RCCs), renal cysts, pancreatic tumors or cysts (PCTs), pheochromocytomas (PHEOs), endolymphatic-sac tumors, and papillary cystadenomas of the epididymis or broad ligament [1,2,3,4,5,6]
The VCB-Cul2 complex leads to the ubiquitination of hypoxia inducible factor (HIF) thereby promoting its degradation in the proteasome [2, 16]. product of the VHL gene (pVHL) inactivation leads to HIF stabilization and activation of downstream target genes that are overexpressed in the highly vascularized tumors that are characteristic of VHL disease [17, 18]

Summary

Introduction

Von Hippel–Lindau disease (VHL; OMIM Number 193300) is an autosomal-dominant inherited tumor predisposition syndrome. The clinical diagnosis of VHL disease can be made if a single VHL associated tumor (hemangioblastoma, PHEO or RCC) occurs in a patient with a family history of VHL [4]. Type 2 was subsequently divided into Type 2A (hemangioblastoma and PHEO but rarely RCC), Type 2B (susceptible to hemangioblastoma, RCC, and PHEO), and Type 2C (PHEO only) [27, 28] These correlations have provided useful strategies for prophylactic surveillance and genetic counseling of asymptomatic members in VHL families. These existing studies are mainly derived from western countries and the genotype-phenotype correlations from Chinese VHL cohorts remain unclear. We analyze a large number of VHL patients to date in order to: (1) analyze how different mutation types of the VHL gene have influenced phenotypes in VHL patients, (2) assess the correlations between mutation regions and phenotypes, and (3) establish genotypephenotype correlations of the disease at codon level

Methods

Results

Conclusion