Somatic mutations in VHL germline deletion kindred correlate with mild phenotype

Abstract

Generally, von Hippel-Lindau (VHL) disease is caused by a germline mutation of the VHL gene (chromosome 3p), and tumorigenesis is initiated from a "second-hit" deletion. A subset of VHL patients have a germline deletion of the VHL gene, and the molecular events leading to tumorigenesis are not fully understood. To determine the molecular pathogenesis of tumor formation in this setting, we analyzed five central nervous system hemangioblastomas from three patients of a single VHL germline deletion kindred, all displaying mild clinical phenotype. Rather than loss of heterozygosity (the "second hit" in VHL germline mutation patients), all tumors from this kindred showed "second-hit" point mutations on the wild-type allele. Moreover, in two patients who each had two hemangioblastomas resected each tumor contained a unique mutation. The specific germline deletion and the overall genetic makeup of the patient did not predict these random "second-hit" point mutations. These results suggest that in patients with germline deletion of a tumor suppressor gene there is a unique genetic mechanism underlying tumorigenesis. This unique genetic mechanism correlates with and may help to understand the mild clinical phenotype seen in these patients.