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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Artículo Open Access |
| Published: |
Wiley
2025
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| Online Access: | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6426 |
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Table of Contents:
- In‐frame insertions of SOX10 are highly enriched and characterize a distinct transcriptomic profile in gastrointestinal schwannomas Pei‐Hang Lee Shih‐Chiang Huang Jen‐Chieh Lee Sung‐Chou Li Jen‐Wei Tsai Yi‐Ming Chang Yu‐Chien Kao Wen‐Lang Fan Ching‐Di Chang Hui‐Chun Chen Chih‐Hao Li Chia‐Fa Hu Ting‐Ting Liu Pao‐Shu Wu Mann‐Hua Nam Shih‐Chen Yu Jui‐Chu Wang Hsuan‐Ying Huang The Journal of Pathology AbstractGastrointestinal 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. 10.1002/path.6426 http://onlinelibrary.wiley.com/termsAndConditions#vor