TY - JOUR AU - Shankar, Ganesh M. AU - Taylor-Weiner, Amaro AU - Lelic, Nina AU - Jones, Robert T. AU - Kim, James C. AU - Francis, Joshua M. AU - Abedalthagafi, Malak AU - Borges, Lawrence F. AU - Coumans, Jean-Valery AU - Curry, William T. AU - Nahed, Brian V. AU - Shin, John H. AU - Paek, Sun Ha AU - Park, Sung-Hye AU - Stewart, Chip AU - Lawrence, Michael S. AU - Cibulskis, Kristian AU - Thorner, Aaron R. AU - Van Hummelen, Paul AU - Stemmer-Rachamimov, Anat O. AU - Batchelor, Tracy T. AU - Carter, Scott L. AU - Hoang, Mai P. AU - Santagata, Sandro AU - Louis, David N. AU - Barker, Fred G. AU - Meyerson, Matthew AU - Getz, Gad AU - Brastianos, Priscilla K. AU - Cahill, Daniel P. PY - 2014 DA - 2014/12/24 TI - Sporadic hemangioblastomas are characterized by cryptic VHL inactivation JO - Acta Neuropathologica Communications SP - 167 VL - 2 IS - 1 AB - 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. SN - 2051-5960 UR - https://doi.org/10.1186/s40478-014-0167-x DO - 10.1186/s40478-014-0167-x ID - Shankar2014 ER -