Somatic Mosaic SOX10 Indel Mutations Underlie a Form of Segmental Schwannomatosis

UCSF, CA, USA

Merryl Terry, Rohit Gupta, Ajay Ravindranathan, Jasper Wu, Emily Chan, Andrew W. Bollen, Susan M. Chang, Mitchel S. Berger and David A. Solomon

While the majority of schwannoma nerve sheath tumors are solitary sporadic tumors, a subset arise as part of heritable tumor predisposition syndromes termed schwannomatosis. Neurofibromatosis type 2 (NF2, also now termed NF2-related schwannomatosis) is an autosomal dominant syndrome caused by heterozygous germline mutation in the NF2 gene on chromosome 22q12.2, which encodes the Merlin protein. Patients with NF2 often develop bilateral vestibular schwannomas, as well as non-vestibular schwannomas, multiple meningiomas, and spinal ependymomas. Two other forms of autosomal dominant schwannomatosis are caused by heterozygous germline mutations in either the SMARCB1 gene on chromosome 22q11.23 (which encodes the chromatin remodeling factor INI1/BAF47) or the LZTR1 gene on chromosome 22q11.21 (which encodes a substrate-specific adaptor of CUL3-dependent ubiquitin ligase that negatively regulates Ras signaling). Patients with SMARCB1- and LZTR1-associated schwannomatosis often develop multiple painful non-vestibular schwannomas in the absence of meningiomas or other tumor types. Germline mutation/deletion of the CDKN2A gene on chromosome 9p21.3 (which encodes a negative regulator of the cell cycle p16INK4a) or the DGCR8 gene on chromosome 22q11.21 (which encodes a subunit of the microRNA processing complex) causes rare tumor predisposition syndromes that may be associated with development of multiple schwannoma or schwannoma-like nerve sheath tumors. However, many patients and families with schwannomatosis do not have identifiable germline variants in NF2, SMARCB1, LZTR1, CDKN2A, or DGCR8, and efforts have been underway to identify other responsible molecular drivers of schwannoma predisposition. While some individuals develop multiple schwannomas diffusely throughout the peripheral nervous system due to a germline mutation in one of the known schwannomatosis genes, other individuals develop multiple schwannomas that are limited to a segment of the body. Such “segmental schwannomatosis” is presumed to be caused by somatic mosaicism (also termed constitutional mosaicism or post-zygotic mosaicism) for a mutation acquired during embryogenesis or perhaps later during postnatal life. The exact nature of such segmental schwannomatosis including the responsible molecular drivers and their timing of acquisition during human life are not well defined. Here, we report identification of somatic mosaicism for SOX10 indel mutations as the genetic alteration underlying a form of segmental schwannomatosis.