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.

purposevon Hippel-Lindau (VHL) syndrome-related renal cell carcinoma (RCC) is the most prevalent hereditary RCC and exhibits clinical heterogeneity, complicating patient management. While

methods115 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

results42.6% 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

conclusionsGermline 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.