A vitronectin M381T polymorphism increases risk of hemangioblastoma in patients with VHL gene defect

Hemangioblastomas, highly vascular tumors, occur sporadically or associated with von Hippel-Lindau (VHL) disease. Diverse mutations in the VHL gene inactivate the VHL protein and constitute the molecular etiology of the disease. Changes in VHL gene were analyzed in patients with multiplex ligation-dependent probe amplification and single-strand conformation polymorphism analyses. We report here that other angiogenesis-related changes in vitronectin were identified with 2D electrophoresis of plasma samples and restriction fragment length polymorphisms. Our findings revealed that most patients (80.0%) with a familial VHL deletion carried the threonine (T) allele at vitronectin codon 381. Adults simultaneously carrying a VHL defect and the T allele were 5.0-fold more likely to be affected by VHL disease than were methionine/methionine (M/M) homozygotes carrying a VHL defect. Patients with sporadic hemangioblastoma, C-terminally truncated VHL protein or a large deletion in the VHL gene, and the T allele were 18.0-fold more likely to develop recurrent disease. Taken together, individuals with mutated VHL are more likely to be affected by familial or recurrent sporadic hemangioblastoma when carrying the M/T or T/T genotype at codon 381 of vitronectin.