Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas

One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology

SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer

Recurrent inactivating mutations in components of SWI/SNF chromatin-remodeling complexes have been identified across cancer types, supporting their roles as tumor suppressors in modulating oncogenic signaling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). We found that SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription in part through regulating expression of Polycomb Repressive Complex component CBX2. Addition of the EGFR inhibitor gefitinib restores the sensitivity of SMARCE1-knockdown cells to MET and ALK inhibitors in NSCLCs. Our findings link SMARCE1 to EGFR oncogenic signaling and suggest targeted treatment options for SMARCE1-deficient tumors