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<p>Neurofibromatosis type 1 (NF1)-associated gastrointestinal stromal tumor (GIST) is a distinct subtype of wild-type GIST driven by loss of neurofibromin function rather than <i>KIT</i> or <i>PDGFRA</i> mutations. Although most NF1-associated GISTs exhibit relatively indolent behavior, a subset demonstrates aggressive progression, and the molecular mechanisms underlying this malignant transformation remain unclear. Here, we report a rare case of NF1-associated gastric GIST with polycomb repressive complex 2 (PRC2)-related epigenetic alteration. A 64-year-old man with NF1 was found to have a small submucosal gastric lesion on screening endoscopy. The tumor enlarged rapidly, and laparoscopic local resection was performed. Histopathological examination confirmed a high-risk gastric GIST with positivity for c-<i>KIT</i>, DOG-1, and CD34. Immunohistochemistry demonstrated preserved SDHB expression but complete loss of H3K27me3. Comprehensive genomic profiling revealed <i>CDKN2A</i> loss, <i>CDKN2B</i> loss, <i>EED</i> loss, and <i>MYC</i> amplification, without pathogenic mutations in <i>KIT</i> or <i>PDGFRA</i>. Despite surgery and tyrosine kinase inhibitor therapy, the tumor rapidly progressed with peritoneal dissemination and malignant pleural effusion, and the patient died 17 months after surgery. This case highlights a possible association between secondary genomic alterations, PRC2-related epigenetic alteration, and aggressive tumor behavior in NF1-associated GIST. Integrated genomic and epigenomic evaluations may provide important insights into tumor behavior and therapeutic strategies for this rare GIST subtype.</p>

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Neurofibromatosis type 1–associated gastric gastrointestinal stromal tumor with PRC2 loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Masaya Iwamuro,
  • Takehiro Tanaka,
  • Shinsuke Hashida,
  • Duy Hung Ngo,
  • Yusuke Aya,
  • Chihiro Sakaguchi,
  • Yoshiyasu Kono,
  • Hidetaka Yamamoto,
  • Motoyuki Otsuka

摘要

Neurofibromatosis type 1 (NF1)-associated gastrointestinal stromal tumor (GIST) is a distinct subtype of wild-type GIST driven by loss of neurofibromin function rather than KIT or PDGFRA mutations. Although most NF1-associated GISTs exhibit relatively indolent behavior, a subset demonstrates aggressive progression, and the molecular mechanisms underlying this malignant transformation remain unclear. Here, we report a rare case of NF1-associated gastric GIST with polycomb repressive complex 2 (PRC2)-related epigenetic alteration. A 64-year-old man with NF1 was found to have a small submucosal gastric lesion on screening endoscopy. The tumor enlarged rapidly, and laparoscopic local resection was performed. Histopathological examination confirmed a high-risk gastric GIST with positivity for c-KIT, DOG-1, and CD34. Immunohistochemistry demonstrated preserved SDHB expression but complete loss of H3K27me3. Comprehensive genomic profiling revealed CDKN2A loss, CDKN2B loss, EED loss, and MYC amplification, without pathogenic mutations in KIT or PDGFRA. Despite surgery and tyrosine kinase inhibitor therapy, the tumor rapidly progressed with peritoneal dissemination and malignant pleural effusion, and the patient died 17 months after surgery. This case highlights a possible association between secondary genomic alterations, PRC2-related epigenetic alteration, and aggressive tumor behavior in NF1-associated GIST. Integrated genomic and epigenomic evaluations may provide important insights into tumor behavior and therapeutic strategies for this rare GIST subtype.