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While the majority of schwannoma nerve sheath tumors are solitary sporadic tumors, a subset arise as part of heritable tumor predisposition syndromes termed schwannomatosis [11]. 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 [16]. Patients with NF2 often develop bilateral vestibular schwannomas, as well as non-vestibular schwannomas, multiple meningiomas, and spinal ependymomas [4]. 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) [7, 10]. Patients with SMARCB1- and LZTR1-associated schwannomatosis often develop multiple painful non-vestibular schwannomas in the absence of meningiomas or other tumor types [8, 14]. 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 [1, 12, 13]. 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 [9, 15, 18]. 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 [11]. 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 [11]. 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.
A 41-year-old female initially presented with progressively worsening left leg and foot pain (Fig. 1a). Examination revealed fullness of the left thigh and an absent left ankle reflex. MR imaging showed several nodular masses along the course of the sciatic nerve in the mid-thigh (Fig. 1b). Following excision, numerous new nodules developed along the length of the left sciatic nerve with a “beads on a string” imaging appearance (Fig. 1b). She underwent four additional surgical excisions over the next 20 years due to continued pain and paresthesia. A second 49-year-old female initially presented with neck and shoulder pain. Imaging revealed two well-circumscribed and anatomically discrete masses in the left neck at levels 2 and 5 along the course of the left spinal accessory nerve (cranial nerve XI, Fig. 1c). She underwent surgical excision of both masses and has remained disease free at 4 years of follow-up. Neither patient had cutaneous neurofibromas, café-au-lait macules, or axillary and inguinal freckling. Neither patient had a family history of nerve sheath tumors. Neither patient had clinical features of Waardenburg syndrome type 4 associated with constitutional defects in the SOX10 gene (Online Mendelian Inheritance in Man # 613266), including sensorineural hearing loss, abnormal pigmentation of the hair and skin, aganglionic megacolon (Hirschsprung disease), peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and seizures/tremors. Histopathologic evaluation of the multiple resected tumors in both patients revealed schwannomas with classic histological features including both compact Antoni A and loose microcystic Antoni B areas, along with diffuse positivity for S100 and SOX10 immunostaining (Fig. 1d, e, Supplementary Figs. S1, S2). There was diffuse positivity for SMARCB1/BAF47/INI1 expression, without the pattern of mosaic loss that has been reported in some schwannomatosis-associated schwannomas (Supplementary Fig. S2) [3].
Genomic analysis was performed on four tumor specimens and adjacent uninvolved sciatic nerve tissue as a source of non-neoplastic constitutional DNA for the first patient, and the two tumor specimens along with both peripheral blood and a skin biopsy specimen as a source of constitutional DNA for the second patient. The multiple tumors from both patients were found to harbor short in-frame insertion/duplication mutations in the SOX10 gene (Supplementary Table S1), similar to those recently discovered in approximately 30% of sporadic solitary schwannomas that were localized at the carboxy-terminal end of the HMG-box DNA binding domain of the encoded homeobox transcription factor (Supplementary Fig. S3) [18]. The first patient harbored a p.Y173_Q174insKY (also annotated as p.K172_Y173dup) mutation that had been found in several sporadic schwannomas, while the second patient harbored a p.R176_R177insQYQPR mutation which was also previously identified in the sporadic schwannoma cohort [18]. The identical SOX10 mutation was present in each of the four tumors from the first patient, and the identical SOX10 mutation was present in both tumors from the second patient (Fig. 1f, g). These SOX10 indel mutations were absent from the non-neoplastic constitutional DNA samples from these patients, thereby proving their somatic origin. No chromosomal copy number aberrations were present beyond monosomy/loss of 22q (Supplementary Table S2), and no other genetic alterations characteristic of nerve sheath tumors were identified involving NF1, NF2, SMARCB1, LZTR1, ERBB2, TRAF7, CDKN2A, TP53, SUZ12, EED, PRKAR1A, or VGLL3 [6, 17]. Genome-wide DNA methylation profiling using the Infinium EPIC Beadchips revealed that these tumors all epigenetically classified as schwannomas (Supplementary Table S3). Furthermore, these tumors clustered together with SOX10-mutant sporadic schwannomas which we previously found are epigenetically distinct from NF2-mutant schwannomas (Supplementary Fig. S4, Supplementary Table S4) [18].
We surmise that the SOX10 indel mutations likely occurred in these patients in a neural crest or Schwann cell progenitor during embryogenesis or early postnatal life. This resulted in individuals that harbor these SOX10 mutations in Schwann cells and their progenitors in a limited segmental distribution along a single peripheral nerve, which then gave rise to multiple genetically identical schwannomas over time. We speculate that the absence of Waardenburg syndrome type 4 clinical features in these individuals is because the somatic mosaicism for the SOX10 indel mutations was limited to a small population of neural crest progenitor cells affecting only a single peripheral nerve and not the central or autonomic nervous systems. The SOX10 gene encodes a homeobox transcription factor known to be critical for differentiation of Schwann cells and maturation to a myelinating cell state [2, 5]. Our prior studies in a fetal glial cell model found that SOX10 indel mutations impair transactivation of glial differentiation and myelination genes, and likely cause schwannoma development through blockade of Schwann cell maturation [18]. Based on the observations in these two patients, we conclude somatic mosaicism for SOX10 indel mutations causes a form of segmental schwannomatosis lacking other known nerve sheath tumor molecular alterations.
Data availability
Raw and processed DNA methylation data from the segmental schwannomatosis tumor cohort has been deposited at the NCBI Gene Expression Omnibus (GEO) under accession number GSE239715. Digitally scanned image files of representative H&E and immunostained sections from the schwannomas are available at the following link: https://figshare.com/projects/Segmental_schwannomatosis/175770. Annotated DNA sequencing data from the schwannoma cohort are provided in the supplementary data tables. Raw sequencing data files are available from the authors upon request.
References
Bahuau M, Vidaud D, Jenkins RB, Bièche I, Kimmel DW, Assouline B et al (1998) Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res 58:2298–2303
Britsch S, Goerich DE, Riethmacher D, Peirano RI, Rossner M, Nave KA et al (2001) The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev 15:66–78. https://doi.org/10.1101/gad.186601
Caltabiano R, Magro G, Polizzi A, Pratico AD, Ortensi A, D’Orazi V et al (2017) A mosaic pattern of INI1/SMARCB1 protein expression distinguishes schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 33:933–940. https://doi.org/10.1007/s00381-017-3340-2
Coy S, Rashid R, Stemmer-Rachamimov A, Santagata S (2020) An update on the CNS manifestations of neurofibromatosis type 2. Acta Neuropathol 139:643–665. https://doi.org/10.1007/s00401-019-02029-5
Finzsch M, Schreiner S, Kichko T, Reeh P, Tamm ER, Bosl MR et al (2010) Sox10 is required for Schwann cell identity and progression beyond the immature Schwann cell stage. J Cell Biol 189:701–712. https://doi.org/10.1083/jcb.200912142
Helbing DL, Schulz A, Morrison H (2020) Pathomechanisms in schwannoma development and progression. Oncogene 39:5421–5429. https://doi.org/10.1038/s41388-020-1374-5
Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (2007) Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 80:805–810. https://doi.org/10.1086/513207
Mansouri S, Suppiah S, Mamatjan Y, Paganini I, Liu JC, Karimi S et al (2021) Epigenomic, genomic, and transcriptomic landscape of schwannomatosis. Acta Neuropathol 141:101–116. https://doi.org/10.1007/s00401-020-02230-x
Paganini I, Chang VY, Capone GL, Vitte J, Benelli M, Barbetti L et al (2015) Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur J Hum Genet 23:963–968. https://doi.org/10.1038/ejhg.2014.220
Piotrowski A, Xie J, Liu YF, Poplawski AB, Gomes AR, Madanecki P et al (2014) Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet 46:182–187. https://doi.org/10.1038/ng.2855
Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO et al (2022) Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med 24:1967–1977. https://doi.org/10.1016/j.gim.2022.05.007
Rivera B, Nadaf J, Fahiminiya S, Apellaniz-Ruiz M, Saskin A, Chong AS et al (2020) DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis. J Clin Invest 130:1479–1490. https://doi.org/10.1172/jci130206
Sargen MR, Kim J, Potjer TP, Velthuizen ME, Martir-Negron AE, Odia Y et al (2023) Estimated prevalence, tumor spectrum, and neurofibromatosis type 1-like phenotype of CDKN2A-related melanoma-astrocytoma syndrome. JAMA Dermatol. https://doi.org/10.1001/jamadermatol.2023.2621
Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L (2008) Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum Mutat 29:227–231. https://doi.org/10.1002/humu.20679
Smith MJ, Wallace AJ, Bowers NL, Rustad CF, Woods CG, Leschziner GD et al (2012) Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 13:141–145. https://doi.org/10.1007/s10048-012-0319-8
Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791–800. https://doi.org/10.1016/0092-8674(93)90501-g
Vasudevan HN, Lucas CG, Villanueva-Meyer JE, Theodosopoulos PV, Raleigh DR (2021) Genetic events and signaling mechanisms underlying Schwann cell fate in development and cancer. Neurosurgery 88:234–245. https://doi.org/10.1093/neuros/nyaa455
Williams EA, Ravindranathan A, Gupta R, Stevers NO, Suwala AK, Hong C et al (2023) Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs. Neuro Oncol. https://doi.org/10.1093/neuonc/noad121
Acknowledgements
We thank the staff of the UCSF Clinical Cancer Genomics Laboratory and the UCSF Histology Laboratory for technical assistance.
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Brain tumor research in the Solomon Lab is supported by the Morgan Adams Foundation, the Yuvaan Tiwari Foundation, the Ross Family, the Panattoni Family Foundation, the UCSF Glioblastoma Precision Medicine Program sponsored by the Sandler Foundation, the UCSF Department of Pathology Experimental Neuropathology Endowment Fund, the UCSF Program for Breakthrough Biomedical Research, and a Developmental Research Program award from the UCSF Brain Tumor SPORE sponsored by the National Cancer Institute, NIH (P50 CA097257).
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D.A.S. is a member of the editorial board of Acta Neuropathologica but was not involved in the handling or decision making for this manuscript. The remaining authors declare that they have no competing interests related to this study.
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Terry, M., Gupta, R., Ravindranathan, A. et al. Somatic mosaic SOX10 indel mutations underlie a form of segmental schwannomatosis. Acta Neuropathol 146, 857–860 (2023). https://doi.org/10.1007/s00401-023-02641-6
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DOI: https://doi.org/10.1007/s00401-023-02641-6