在胃肠道神经鞘瘤中,框架内插入的SOX10高度富集,具有独特的转录组特征。

IF 5.6 2区 医学 Q1 ONCOLOGY
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
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引用次数: 0

摘要

胃肠道神经鞘瘤在分子和组织学上与非胃肠道神经鞘瘤不同,缺乏NF2改变,尽管这些肿瘤的主要驱动因素几乎不为人所知。最近的一项研究已经确定了SOX10在神经鞘瘤中的框架内插入,特别是在颅内非前庭病变中,而它们在胃肠道神经鞘瘤中的作用仍未被探索。对15例胃肠道和2例非胃肠道神经鞘瘤的全外显子组测序显示,14例胃肠道病例(93%)复发性SOX10框架内插入,无其他神经鞘肿瘤相关改变,如NF2突变或SH3PXD2A::HTRA1融合(非胃肠道病例约14%)。在包括61例胃肠道神经鞘瘤和98例非胃肠道神经鞘瘤,以及110例非神经鞘瘤间充质瘤和黑素细胞瘤在内的大型队列中,使用Sanger测序验证了SOX10插入的患病率、突变谱和特异性。与非胃肠道病例(5.1%)相比,胃肠道神经鞘瘤中SOX10插入位点(91.8%)在高迁移性组盒域内或附近显著富集。最常见的插入基因p.Y173_Q174insKY在86.9%的胃肠道神经鞘瘤中存在,但在非胃肠道病例中不存在。另一种复发性插入,p.p p175_r176inskyqp是罕见的,仅在非胃肠道神经鞘瘤中发现(3/98),而所有非神经鞘瘤对照均为sox10正常。插入sox10的神经鞘瘤表现出胃肠道神经鞘瘤的组织学特征,包括雪旺细胞的微小梁排列、外周淋巴细胞袖带和缺乏包被。插入SOX10和正常SOX10神经鞘瘤均表现出弥漫性SOX10免疫反应性。插入sox10组与胃肠道位置显著相关(p
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In-frame insertions of SOX10 are highly enriched and characterize a distinct transcriptomic profile in gastrointestinal schwannomas.

Gastrointestinal 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.

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来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
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