{"title":"携带SH3PXD2A-HTRA1融合基因的脑神经鞘瘤的遗传及临床特征","authors":"Junki Sogano, Ryota Tamura, Masahiro Yo, Kohei Nakamura, Ippei Fukada, Takayuki Ueno, Utaro Hino, Azuna Tomioka, Kosuke Karatsu, Aya Nagao, Ryo Ueda, Hiroshi Nishihara, Masahiro Toda","doi":"10.1007/s00401-025-02941-z","DOIUrl":null,"url":null,"abstract":"<div><p>The <i>SH3PXD2A-HTRA1</i> fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of this fusion gene in intracranial schwannomas, stratified by cranial nerve of origin. We retrospectively investigated the fusion gene in 237 intracranial schwannomas. Fusion detection was performed using reverse transcription polymerase chain reaction and confirmed by Sanger sequencing. Somatic <i>NF2</i> status was evaluated using whole-genome sequencing or Merlin immunohistochemistry in fusion gene-positive cases. Clinical characteristics and postoperative tumor recurrence were compared between fusion gene-positive and fusion gene-negative tumors, and subgroup analyses were performed by cranial nerve of origin. The fusion gene was detected in 30 tumors (12.7%), with the highest frequency observed in trigeminal schwannomas (25.9%). Tumors classified as recurrent at baseline (odds ratio [OR], 3.74; <i>P</i> = 0.012), trigeminal nerve origin (OR, 2.88; <i>P</i> = 0.042), and intratumoral hemorrhage (OR, 18.61; <i>P</i> = 0.028) were significantly associated with fusion gene-positive tumors. In the trigeminal schwannomas, fusion gene-positive cases were significantly younger (<i>P</i> = 0.029). In the vestibular schwannomas, recurrence status was found to be independently associated with positive fusion gene status (OR, 4.53; <i>P</i> = 0.010). Furthermore, even after gross or nearly total resection, fusion gene-positive vestibular schwannomas exhibited a significantly higher incidence of recurrence after surgery (<i>P</i> = 0.046). Only 33% of fusion gene-positive tumors indicated somatic <i>NF2</i> alteration. The <i>SH3PXD2A-HTRA1</i> fusion gene may define a molecular subset of intracranial schwannomas with distinctive anatomical distribution and biological aggressiveness. It may contribute to tumorigenesis through an alternative pathway independent of <i>NF2</i>. Our findings provide a basis for future clinical investigations.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3000,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic and clinical characteristics of cranial nerve schwannoma harboring SH3PXD2A-HTRA1 fusion gene\",\"authors\":\"Junki Sogano, Ryota Tamura, Masahiro Yo, Kohei Nakamura, Ippei Fukada, Takayuki Ueno, Utaro Hino, Azuna Tomioka, Kosuke Karatsu, Aya Nagao, Ryo Ueda, Hiroshi Nishihara, Masahiro Toda\",\"doi\":\"10.1007/s00401-025-02941-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The <i>SH3PXD2A-HTRA1</i> fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of this fusion gene in intracranial schwannomas, stratified by cranial nerve of origin. We retrospectively investigated the fusion gene in 237 intracranial schwannomas. Fusion detection was performed using reverse transcription polymerase chain reaction and confirmed by Sanger sequencing. Somatic <i>NF2</i> status was evaluated using whole-genome sequencing or Merlin immunohistochemistry in fusion gene-positive cases. Clinical characteristics and postoperative tumor recurrence were compared between fusion gene-positive and fusion gene-negative tumors, and subgroup analyses were performed by cranial nerve of origin. The fusion gene was detected in 30 tumors (12.7%), with the highest frequency observed in trigeminal schwannomas (25.9%). Tumors classified as recurrent at baseline (odds ratio [OR], 3.74; <i>P</i> = 0.012), trigeminal nerve origin (OR, 2.88; <i>P</i> = 0.042), and intratumoral hemorrhage (OR, 18.61; <i>P</i> = 0.028) were significantly associated with fusion gene-positive tumors. In the trigeminal schwannomas, fusion gene-positive cases were significantly younger (<i>P</i> = 0.029). In the vestibular schwannomas, recurrence status was found to be independently associated with positive fusion gene status (OR, 4.53; <i>P</i> = 0.010). Furthermore, even after gross or nearly total resection, fusion gene-positive vestibular schwannomas exhibited a significantly higher incidence of recurrence after surgery (<i>P</i> = 0.046). Only 33% of fusion gene-positive tumors indicated somatic <i>NF2</i> alteration. The <i>SH3PXD2A-HTRA1</i> fusion gene may define a molecular subset of intracranial schwannomas with distinctive anatomical distribution and biological aggressiveness. It may contribute to tumorigenesis through an alternative pathway independent of <i>NF2</i>. Our findings provide a basis for future clinical investigations.</p></div>\",\"PeriodicalId\":7012,\"journal\":{\"name\":\"Acta Neuropathologica\",\"volume\":\"150 1\",\"pages\":\"\"},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2025-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Neuropathologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00401-025-02941-z\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-025-02941-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
SH3PXD2A-HTRA1融合基因最近在神经鞘瘤的一个亚群中被发现,但其频率和临床意义尚不清楚。本研究旨在探讨该融合基因在颅内神经鞘瘤中的流行程度及其临床意义,并以颅神经来源分层。我们回顾性研究了237例颅内神经鞘瘤的融合基因。采用逆转录聚合酶链反应进行融合检测,并通过Sanger测序进行确认。融合基因阳性病例的体细胞NF2状态采用全基因组测序或Merlin免疫组织化学进行评估。比较融合基因阳性与融合基因阴性肿瘤的临床特征及术后肿瘤复发率,并以颅神经为起始点进行亚组分析。在30例肿瘤(12.7%)中检测到融合基因,其中三叉神经鞘瘤的频率最高(25.9%)。基线时复发的肿瘤(优势比[OR], 3.74; P = 0.012)、三叉神经来源的肿瘤(优势比[OR], 2.88; P = 0.042)和瘤内出血(优势比[OR], 18.61; P = 0.028)与融合基因阳性肿瘤相关。在三叉神经鞘瘤中,融合基因阳性的病例明显年轻化(P = 0.029)。在前庭神经鞘瘤中,复发状态与融合基因阳性状态独立相关(OR, 4.53; P = 0.010)。此外,即使在完全或几乎完全切除后,融合基因阳性的前庭神经鞘瘤术后复发率也明显更高(P = 0.046)。只有33%的融合基因阳性肿瘤显示体细胞NF2改变。SH3PXD2A-HTRA1融合基因可能定义了具有独特解剖分布和生物侵袭性的颅内神经鞘瘤的分子亚群。它可能通过独立于NF2的替代途径促进肿瘤发生。我们的发现为今后的临床研究提供了基础。
Genetic and clinical characteristics of cranial nerve schwannoma harboring SH3PXD2A-HTRA1 fusion gene
The SH3PXD2A-HTRA1 fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of this fusion gene in intracranial schwannomas, stratified by cranial nerve of origin. We retrospectively investigated the fusion gene in 237 intracranial schwannomas. Fusion detection was performed using reverse transcription polymerase chain reaction and confirmed by Sanger sequencing. Somatic NF2 status was evaluated using whole-genome sequencing or Merlin immunohistochemistry in fusion gene-positive cases. Clinical characteristics and postoperative tumor recurrence were compared between fusion gene-positive and fusion gene-negative tumors, and subgroup analyses were performed by cranial nerve of origin. The fusion gene was detected in 30 tumors (12.7%), with the highest frequency observed in trigeminal schwannomas (25.9%). Tumors classified as recurrent at baseline (odds ratio [OR], 3.74; P = 0.012), trigeminal nerve origin (OR, 2.88; P = 0.042), and intratumoral hemorrhage (OR, 18.61; P = 0.028) were significantly associated with fusion gene-positive tumors. In the trigeminal schwannomas, fusion gene-positive cases were significantly younger (P = 0.029). In the vestibular schwannomas, recurrence status was found to be independently associated with positive fusion gene status (OR, 4.53; P = 0.010). Furthermore, even after gross or nearly total resection, fusion gene-positive vestibular schwannomas exhibited a significantly higher incidence of recurrence after surgery (P = 0.046). Only 33% of fusion gene-positive tumors indicated somatic NF2 alteration. The SH3PXD2A-HTRA1 fusion gene may define a molecular subset of intracranial schwannomas with distinctive anatomical distribution and biological aggressiveness. It may contribute to tumorigenesis through an alternative pathway independent of NF2. Our findings provide a basis for future clinical investigations.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.