Somatic mutational landscape in von Hippel–Lindau familial hemangioblastoma

Von Hippel-Lindau disease (vHL) predisposes to tumor development, mainly clear cell renal carcinoma and hemangioblastoma. The underlying cause is germline variants in the VHL gene, with tumorigenesis thought to require additional somatic 'second-hit' events that most commonly include loss of 3p. However, the precise mechanisms of vHL-related tumor development remain incompletely understood. Genomic investigations of familial hemangioblastoma may help elucidate the early steps of tumorigenesis and contribute to improved disease prediction, biomarker discovery, and therapeutic strategies. We performed whole exome sequencing on 22 familial hemangioblastomas from 7 patients representing 5 unrelated families, and with 4 different causative VHL genotypes. The tumors exhibited low overall mutational burden but showed frequent loss of heterozygosity on chromosome 3 or 3p and single nucleotide variants in the VHL region. Variants were significantly enriched in genes associated with GABAergic and serotonergic neuronal cell types, as well as in pathways regulating cell cycle and neurogenesis. These findings suggest that, in addition to VHL loss, dysregulation of neuronal differentiation programs and cell cycle control may play important roles in hemangioblastoma tumorigenesis.