Abstract A35: SMARCE1 mutations cause inherited multiple spinal meningiomas

Meningiomas represent approximately one third of all primary central nervous system tumors in adults. Multiple meningiomas are usually associated with neurofibromatosis type 2 (NF2) disease, which is caused by mutations in the NF2 gene. Recent reports have also shown multiple meningiomas to be associated with schwannomatosis disease, which is caused by mutations in the SWI/SNF chromatin remodeling complex subunit, SMARCB1. In a subset of individuals, multiple meningioma disease is a discrete entity, inherited in an autosomal dominant manner unrelated to NF2 or SMARCB1 mutations. We sought to discover novel genes associated with a predisposition to meningioma development by exome sequencing of germline DNA three unrelated individuals with familial multiple spinal meningiomas, who did not have germline NF2 or SMARCB1 mutations. Two of these three individuals harbored heterozygous novel loss-of-function mutations in the SWI/SNF complex subunit, SMARCE1. Sanger sequencing of SMARCE1 in lymphocyte DNA from six additional individuals with spinal meningiomas identified another two novel heterozygous loss-of-function mutations. Tumors from individuals with germline SMARCE1 mutations were demonstrated a clear cell histological subtype and all demonstrated loss of SMARCE1 protein consistent with a tumor suppressor mechanism. Our findings define multiple spinal meningioma disease as a novel discrete entity and implicate the SWI/SNF chromatin remodeling complex in the pathogenesis of meningiomas and tumors with clear cell histology. Citation Format: Miriam J. Smith, James O'Sullivan, Sanjeev S. Bhaskar, Kristen D. Hadfield, Gemma Poke, John Caird, Saba Sharif, Diana Eccles, David FitzPatrick, Daniel Rawluk, Daniel du Plessis, William G. Newman, D. Gareth Evans. SMARCE1 mutations cause inherited multiple spinal meningiomas. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A35.