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<p><i>NF2</i>-related schwannomatosis (<i>NF2</i>-SWN) is a genetic predisposition syndrome characterized by the development of bilateral vestibular schwannomas (VSs). Despite their benign nature and consistent histopathological characteristics, these tumours display significant clinical and therapeutic heterogeneity. To elucidate the molecular heterogeneity within <i>NF2</i>-SWN schwannomas, we performed comprehensive molecular analyses on a cohort of 70 patients with <i>NF2</i>-SWN, including bulk RNA sequencing, whole genome or exome sequencing, single nuclear RNA (snRNA) sequencing and immunohistochemistry. Our analysis identified two distinct molecular subgroups: immune-enriched schwannomas (IESs) and immune-depleted schwannomas (IDSs). IESs were commonly diagnosed in adulthood, followed a favorable prognosis, and were characterized by abundant macrophage infiltration within the tumour microenvironment. In contrast, IDSs were predominantly composed of Schwann cells, harbored germline <i>NF2</i> mutations, occurred primarily during childhood and had poorer outcomes. Immunohistochemical staining for ionized calcium-binding adaptor molecule 1 (Iba1) and CD68, CD163 antibodies effectively differentiated these two subgroups of <i>NF2</i>-SWN schwannomas. Furthermore, we demonstrated that blockade of the colony stimulating factor 1 receptor (CSF1R) resulted in macrophage depletion and significantly suppressed tumour growth in both in vitro and in vivo models of IESs. Collectively, our study reveals two discrete molecular subgroups within <i>NF2</i>-SWN schwannomas, highlighting the importance of considering these subgroups in future therapeutic research and clinical trial design.</p>

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Multiplatform molecular analyses reveal two molecular subgroups of NF2-related schwannomatosis vestibular schwannomas with distinct tumour microenvironment and therapeutic vulnerabilities

  • 期刊论文

  • 发表日期：

    2025年5月9日

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  • Fu Zhao,
  • Xu-Fei Teng,
  • Jing Zhang,
  • Shi-Wei Li,
  • Lei-Ming Wang,
  • Han-Guang Zhao,
  • Shun Zhang,
  • Chi Zhao,
  • Peng Li,
  • Xiao-Bin Zhao,
  • Shu-Hui Song,
  • Pi-Nan Liu

摘要

NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition syndrome characterized by the development of bilateral vestibular schwannomas (VSs). Despite their benign nature and consistent histopathological characteristics, these tumours display significant clinical and therapeutic heterogeneity. To elucidate the molecular heterogeneity within NF2-SWN schwannomas, we performed comprehensive molecular analyses on a cohort of 70 patients with NF2-SWN, including bulk RNA sequencing, whole genome or exome sequencing, single nuclear RNA (snRNA) sequencing and immunohistochemistry. Our analysis identified two distinct molecular subgroups: immune-enriched schwannomas (IESs) and immune-depleted schwannomas (IDSs). IESs were commonly diagnosed in adulthood, followed a favorable prognosis, and were characterized by abundant macrophage infiltration within the tumour microenvironment. In contrast, IDSs were predominantly composed of Schwann cells, harbored germline NF2 mutations, occurred primarily during childhood and had poorer outcomes. Immunohistochemical staining for ionized calcium-binding adaptor molecule 1 (Iba1) and CD68, CD163 antibodies effectively differentiated these two subgroups of NF2-SWN schwannomas. Furthermore, we demonstrated that blockade of the colony stimulating factor 1 receptor (CSF1R) resulted in macrophage depletion and significantly suppressed tumour growth in both in vitro and in vivo models of IESs. Collectively, our study reveals two discrete molecular subgroups within NF2-SWN schwannomas, highlighting the importance of considering these subgroups in future therapeutic research and clinical trial design.