Journal of Neuro-Oncology 52: 241–247, 2001. © 2001 Kluwer Academic Publishers. Printed in the Netherlands. Clinical Study Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization Sandra H.E. Sprenger 1 , Johanna M.M. Gijtenbeek 1 , Pieter Wesseling 1,2 , Raf Sciot 3 , Frank van Calenbergh 4 , Martin Lammens 1,2 and Judith W. M. Jeuken 1 1 Department of Neurology, 2 Department of Pathology, University Medical Center Nijmegen, Nijmegen, The Netherlands; 3 Department of Pathology, 4 Department of Neurosurgery, University Hospital K.U. Leuven, Belgium Key words: CGH, chromosome 3, chromosome 6, hemangioblastomas, oncogenesis, sporadic Summary Hemangioblastomas (HBs) of the central nervous system are benign tumors and occur as sporadic (sp) tumors (75%) or as a manifestation of the von Hippel-Lindau (VHL) disease (25%). VHL-disease is an autosomal dominant disorder characterized by HBs of the central nervous system and retina, renal cell carcinoma (RCC), phaeochro- mocytoma (PHEO), islet tumors of the pancreas, and endolympatic sac tumors as well as cysts and cystadenoma in the kidney, pancreas and epididymis. In VHL patients a large spectrum of germline mutations in the VHL gene has been detected. In spHBs VHL alleles are reported to be inactivated in up to 50% of the tumors. To our knowledge the involvement of other genes in spHBs has not been investigated. To elucidate the oncogenesis of spHBs, we performed CGH on 10 spHBs to screen for chromosomal imbalances throughout the entire tumor genome. Aber- rations most frequently detected are losses of chromosomes 3 (70%), 6 (50%), 9 (30%), and 18q (30%) and a gain of chromosome 19 (30%). Based on these frequencies and the co-occurrence of these aberrations in the analyzed tumors we hypothesize that loss of chromosome 3 (harboring the VHL gene) is an early event in the oncogenesis of spHBs, followed by loss of 6, and then losses of chromosomes 9, 18q and gain of chromosome 19. Comparison of the chromosomal imbalances in spHBs to those previously reported in RCCs and PHEOs reveals that the pathway of spHBs shows similarities to both the RCCs and PHEOs. Introduction Hemangioblastomas (HBs) are benign, highly vascu- larized neoplasms of the central nervous system, which account for only 1–2% of all intracranial tumors. The origin of the tumor cells in spHBs is still unknown [1]. HBs occur as sporadic tumors (spHB) (75%) or as part of von Hippel-Lindau (VHL-HB) disease (25%). VHL-disease is an autosomal dominant disor- der characterized by HBs of the central nervous system and retina, renal cell carcinoma (RCC), phaeochro- mocytoma (PHEO), islet tumors of the pancreas, and endolympatic sac tumors as well as cysts and cystadenoma in the kidney, pancreas and epididymis [2,3]. A large spectrum of germline mutations in the VHL tumor suppressor gene, located at chromosome 3p25 [4] has been detected in VHL patients [5–8]. The VHL-protein (pVHL) is involved in transcription elongation [9] and in regulation of stability of hypoxia inducible factors such as vascular endothelial growth factor (VEGF) [10]. Inactivation of the VHL gene also plays a role in part of the sporadic counterparts of the tumors observed in VHL disease. In spHBs somatic mutations of the VHL gene have been reported in up to 50% [5–8] and a loss of heterozygosity including the VHL region is reported in the stromal cell component of 50% [7]. To our knowledge the involvement of other genes in spHBs has not been investigated. We used Comparative Genomic Hybridization (CGH) [11,12] to screen for chromosomal imbalances throughout the entire tumor genome of spHBs to elucidate which chromosomal