Lee, Pei-HangPei-HangLeeHuang, Shih-ChiangShih-ChiangHuangJEN-CHIEH LEELi, Sung-ChouSung-ChouLiTsai, Jen-WeiJen-WeiTsaiChang, Yi-MingYi-MingChangKao, Yu-ChienYu-ChienKaoFan, Wen-LangWen-LangFanChang, Ching-DiChing-DiChangChen, Hui-ChunHui-ChunChenLi, Chih-HaoChih-HaoLiHu, Chia-FaChia-FaHuLiu, Ting-TingTing-TingLiuWu, Pao-ShuPao-ShuWuNam, Mann-HuaMann-HuaNamYu, Shih-ChenShih-ChenYuWang, Jui-ChuJui-ChuWangHuang, Hsuan-YingHsuan-YingHuang2025-05-262025-05-262025-04-24https://scholars.lib.ntu.edu.tw/handle/123456789/729683Gastrointestinal schwannomas are molecularly and histologically distinct from their non-gastrointestinal counterparts, lacking NF2 alterations, although the primary drivers of these tumors are barely understood. A recent study has identified SOX10 in-frame insertions in schwannomas, particularly in intracranial non-vestibular lesions, whereas their role in gastrointestinal schwannomas remains unexplored. Whole exome sequencing of 15 gastrointestinal and two non-gastrointestinal schwannomas revealed recurrent SOX10 in-frame insertions in 14 gastrointestinal cases (93%) without other nerve sheath tumor-related alterations, such as NF2 mutations or SH3PXD2A::HTRA1 fusions (~14% in non-gastrointestinal cases). The prevalence, mutation spectrum, and specificity of SOX10 insertions were validated using Sanger sequencing in a large cohort comprising 61 gastrointestinal and 98 non-gastrointestinal schwannomas, as well as 110 non-schwannomatous mesenchymal and melanocytic neoplasms. SOX10 insertions, occurring within or near the high mobility group box domain, were significantly enriched in gastrointestinal schwannomas (91.8%) compared with non-gastrointestinal cases (5.1%). The most common insertion, p.Y173_Q174insKY, was present in 86.9% of gastrointestinal schwannomas but absent in non-gastrointestinal cases. Another recurrent insertion, p.P175_R176insKYQP, was rare and exclusively found in non-gastrointestinal schwannomas (3/98), while all non-schwannomatous controls were SOX10-normal. SOX10-inserted schwannomas exhibited histologic features characteristic of gastrointestinal schwannomas, including a microtrabecular arrangement of Schwann cells, peripheral lymphoid cuffs, and a lack of encapsulation. Both SOX10-inserted and SOX10-normal schwannomas demonstrated diffuse SOX10 immunoreactivity. The SOX10-inserted group was significantly associated with gastrointestinal locations (p < 0.001), older patients (p < 0.001), fusion negativity (p < 0.001), and larger tumor size (p = 0.013). Gene expression profiling of 44 cases revealed distinct transcriptomic profiles between primarily SOX10-inserted and SOX10-normal groups, with the latter group being classifiable into fusion-poor and fusion-enriched sub-clusters. This study highlights the genetic heterogeneity of schwannomas and suggests that SOX10 insertions play a pivotal role in the tumorigenesis of gastrointestinal schwannomas, distinctly separating them from non-gastrointestinal counterparts and contributing to their unique molecular profile. © 2025 The Pathological Society of Great Britain and Ireland.enNF2 mutationSH3PXD2A::HTRA1 fusionSOX10 insertiongastrointestinal schwannomagenetic heterogeneityhigh mobility group box domainhistologymolecular pathogenesistranscriptomic profilewhole exome sequencing[SDGs]SDG3journal article10.1002/path.642640272443