Abstract B011: Common VHL mutations and the genotype-phenotype correlation: A retrospective study of 1172 patients with von Hippel-Lindau syndrome in China

Introduction & Objectives Von Hippel-Lindau (VHL) syndrome is a hereditary disorder characterized by multiple tumors affecting various organs, including renal cell carcinoma, pancreatic cysts or tumors, cerebellar hemangioblastomas, retinal angiomas, and pheochromocytomas. It is caused by mutations in the VHL gene. Despite the same underlying genetic mutations, the pathogenesis, clinical features, and prognosis of affected patients can differ significantly. This study focuses on the most frequent mutations in the VHL gene, outlining the mutation spectrum in VHL syndrome and exploring the correlation between specific mutations and the development of renal cell carcinoma. Materials & Methods This study included 1172 patients with VHL syndrome from 486 unrelated families, all of whom were diagnosed at Peking University First Hospital up to December 25, 2024. After excluding patients with incomplete clinical data, 1103 patients from 462 unrelated families were used for the genotype-phenotype analysis. Results The most common mutation type identified was missense mutations (49.6%), followed by large deletions (17.5%), small fragment deletions/insertions (15.8%), nonsense mutations (12.1%), and splice site mutations (4.8%). The mutation sites were primarily located within the pVHL protein at the HIFα and Elongin C binding regions. The most frequent mutations by type included: missense mutation: c.499C>T; small fragment deletion/insertion: c.224-6delTCT; nonsense mutation: c.481C>T; splicing mutation: c.463+1G>A; and large fragment deletion: exon 2 deletion. Cerebellar hemangioblastoma was the most prevalent clinical manifestation in patients with VHL syndrome (61.0%), followed by renal cell carcinoma (53.5%). Additionally, 61.3% of patients exhibited two or more concurrent conditions. Further analysis of high-frequency mutations and their association with renal cell carcinoma showed that missense mutation c.486C>G (71.4%), large fragment deletion of exon 3 (75.0%), and nonsense mutation c.481C>T (70.0%) were linked to a higher incidence of renal cell carcinoma. Logistic regression analysis revealed that large fragment deletion of exon 3 was associated with a higher risk of renal cell carcinoma compared to other mutation types (OR: 2.866, 95% CI: 1.070–7.677, P=0.031). Conclusions The type and location of high-frequency mutations in the VHL gene are closely correlated with specific phenotypic manifestations. Future genotype-phenotype studies should focus on the functional domains of the VHL gene, and further investigation into the molecular mechanisms underlying these genotype-phenotype correlations is needed. Citation Format: Chuandong Wang, Kan Gong. Common VHL mutations and the genotype-phenotype correlation: A retrospective study of 1172 patients with von Hippel-Lindau syndrome in China [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B011.