{"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}
引用次数: 0
Abstract
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.