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<p>H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1/H3.2-mutant, H3-wildtype with EZHIP overexpression, and <i>EGFR</i>-mutant. <i>H3F3B</i>, another gene encoding histone H3.3 in addition to <i>H3F3A</i>, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of <i>H3F3B</i>-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with <i>H3F3B</i>-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic <i>H3F3B</i> p.K27I mutation. Average patient age was 46 ± 6.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that <i>H3F3B</i>-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. <i>PPM1D</i> and <i>NF1</i> were frequently mutated in <i>H3F3B</i>-mutant DMGs. Survival analysis showed that <i>H3F3B</i>-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, <i>H3F3B</i> mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between <i>H3F3B</i>-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.</p>

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H3F3B p.K27I-mutant diffuse midline glioma is a distinct subtype of H3K27-altered diffuse midline glioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月23日

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  • Lei Cheng,
  • Min Zhou,
  • Tao Luo,
  • Rongfang Dong,
  • Ni Chen,
  • Xinyong Cai,
  • Xingwen Wang,
  • Hao Wu,
  • Zan Chen,
  • Zuowei Wang,
  • Xueling Qi,
  • Dehong Lu,
  • Lianghong Teng,
  • Fengzeng Jian,
  • Leiming Wang

摘要

H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1/H3.2-mutant, H3-wildtype with EZHIP overexpression, and EGFR-mutant. H3F3B, another gene encoding histone H3.3 in addition to H3F3A, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of H3F3B-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with H3F3B-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic H3F3B p.K27I mutation. Average patient age was 46 ± 6.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that H3F3B-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. PPM1D and NF1 were frequently mutated in H3F3B-mutant DMGs. Survival analysis showed that H3F3B-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, H3F3B mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between H3F3B-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.