OS08.7 The somatic landscape of Schwannoma

AbstractTo date, clinical trials for schwannomas, which are common cranial and spinal nerve tumors, have generated dismal results. This is largely due to a lack of fully understanding the somatic alterations that occur in schwannoma. To gain a comprehensive molecular understanding of Schwannoma, we performed an integrative multiplatform analysis to determine the genetic landscape of sporadic schwannomas. Exome sequence analysis with validation by targeted DNA-sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. Genome wide methylation profiling revealed that schwannomas consists of two molecular subgroups with unique gene signatures and anatomical location. RNA sequencing revealed a recurrent in-frame gene fusion on chromosome 10q in 12/125 (10%) cases involving two gene partners, SH3PXD2A and HTRA1. Further genomic analysis identified the mechanism to be from a balanced 19Mb chromosomal inversion. The presence of the fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Expression of the fusion in both schwannomas and normal schwann cells resulted in elevated phosphorylated-ERK, increased proliferation, increased invasion and resulted in the formation of in vivo xenografts. Furthermore, the fusion increased cell invasion and enhanced protease activity. Targeting of the MEK/ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.