Abstract
Hemangioblastomas consist of 10-20% neoplastic “stromal” cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0167-x) contains supplementary material, which is available to authorized users.
Highlights
Hemangioblastomas comprise 1–2.5% of primary intracranial and 7-10% of spinal cord tumors, with a benign pathology notable for neoplastic “stromal” cells embedded in a dense network of vascular channels [1]
Patients were identified as likely sporadic hemangioblastomas based on (1) prior testing that was negative for germline Von Hippel-Lindau (VHL) mutations by sequencing of the coding regions, (2) lack of family history of hemangioblastomas or VHL disease, and/or (3) lack of other stigmata of VHL disease, such as renal cancer, pheochromocytoma, or retinal angiomas
whole exome sequencing (WES) of germline DNA from the discovery cohort did not reveal any VHL mutations, indicating that these patients do not have VHL disease and that the tumors we evaluated are bona fide sporadic hemangioblastomas
Summary
Hemangioblastomas comprise 1–2.5% of primary intracranial and 7-10% of spinal cord tumors, with a benign pathology notable for neoplastic “stromal” cells embedded in a dense network of vascular channels [1]. Unlike in familial VHL disease, prior studies have indicated that the majority of sporadic hemangioblastomas do not have identifiable germline or somatic alterations in VHL (Table 1). This discrepancy stands in contrast to recent whole genome characterization of clear cell renal carcinomas, which have somatic mutations in the VHL gene in >80% of samples [11,12], focal deletion by loss of chromosome 3p26.1 in >90% [13], or epigenetic silencing by promoter methylation in 7% [13]
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