Novel genetic characterisation and phenotype correlation in von Hippel-Lindau (VHL) disease based on the Elongin C binding site: a large retrospective study

Abstract

BackgroundVon 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.MethodsThis 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.ResultsA 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.ConclusionIn 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.

Metabolomic landscape of renal cell carcinoma in von Hippel-Lindau syndrome in a Chinese cohort

“… 78 Additionally, various mutation types in this gene were found to be associated with different prognoses among patients. 79 Interestingly, in this study, we unexpectedly observed a connection between different mutation locations in the VHL gene and the levels of certain DAMs in plasma ( Figures 8 , S3 ). Notably, distinct mutation locations resulted in variations in the same metabolite levels.…”

Genetics, Pathophysiology, and Current Challenges in Von Hippel-Lindau Disease Therapeutics

“…If the person has an uncle, cousin, or grandparent with VHL, they are also at risk for developing VHL. Moreover, it has been reported the presence of the disease in individuals without family background, therefore it is necessary a differential diagnosis in each individual [30].…”

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

“…However, all patients were enrolled in VHL-disease surveillance protocol. A large study, that included 533 patients with VHL disease, evaluated the correlation between developing VHL-related tumors and the type of VHL mutations [ 133 ]. The researchers found that truncating and missense mutations in non-Elongin-C binding sites conferred a high risk for the development of CNS hemangioblastomas.…”