Comparison of clinical characteristics between patients with single mutation and co-mutation in hereditary renal cancer: a retrospective analysis of 115 patients with von Hippel-Lindau syndrome

Purpose von Hippel-Lindau (VHL) syndrome-related renal cell carcinoma (RCC) is the most prevalent hereditary RCC and exhibits clinical heterogeneity, complicating patient management. While VHL gene inactivation is the primary driver, the impact of co-occurring germline mutations in other renal cancer predisposition genes on clinical phenotype remains poorly understood. This study aimed to investigate whether such co-mutations define a distinct clinical and molecular subgroup of patients with VHL syndrome. Methods 115 patients with VHL syndrome were enrolled in this study. All patients underwent germline sequencing of a 39-gene panel for hereditary RCC. Pathogenic/likely pathogenic variants of the VHL gene were identified, and patients were stratified into a VHL single-mutation group and a VHL co-mutation group. Clinical characteristics, tumour manifestations, renal lesion growth kinetics and age-related tumour risks were compared. Results 42.6% of patients harboured germline co-mutations. The co-mutation group exhibited a greater proportion of symptomatic patients (95.9% vs 78.7%, p=0.012) and increased penetrance of RCC (79.6% vs 57.6%, p=0.013) and pancreatic cystic tumours (77.6% vs 48.5%, p=0.002). This group had a lower incidence of positive family history (40.8% vs 69.7%, p=0.002). Co-mutation status is an independent predictor for RCC development (HR 1.798, p=0.016), and their RCC lesions exhibited significantly faster linear (0.376 cm/year vs 0.225 cm/year, p=0.022) and volumetric (3.132 cm 3 /year vs 1.167 cm 3 /year, p=0.049) growth metrics. Conclusions Germline co-mutations are prevalent in VHL syndrome and define a clinically distinct subset of patients characterised by higher disease penetrance and a more aggressive RCC phenotype. Our findings suggest that co-mutation status is a critical determinant of clinical heterogeneity and a powerful biomarker for risk stratification.