Loss of Heterozygosity at 6q Is Frequent and Concurrent with 3p Loss in Sporadic and Familial Capillary Hemangioblastomas

Abstract

Capillary hemangioblastoma is a benign tumor, occurring sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Inactivation of the VHL gene at 3p25-26 has been demonstrated in all VHL-associated hemangioblastomas. However, the VHL gene has been found to be inactivated in only 20% to 50% of sporadic tumors. So far, no other gene has been reported to be involved in the development of hemangioblastomas. DNA losses at 6q are frequent alterations in hemangioblastomas, as shown by comparative genomic hybridization. We therefore analyzed 15 hemangioblastomas for loss of heterozygosity (LOH) on chromosome 3p and 6q to reveal the frequency of allelic losses and to determine minimal deleted areas. We detected LOH at 6q for one or more markers in 11 (73%) out of 15 cases (in 9 of 11 sporadic and in 2 of 4 VHL-associated tumors). The analyses revealed a minimal 3-megabase (Mb) deleted region at 6q23-24, where 9 of 11 (82%) informative cases showed LOH. LOH at 3p was seen in 14 out of 15 tumors. LOH occurred concurrently at 6q and 3p in 67% of cases. Our data strongly suggests that a tumor suppressor gene located at 6q23-24 is involved in tumorigenesis of hemangioblastomas, in addition to the VHL gene.