Cheng Lei, Zhou Min, Luo Tao, Dong Rongfang, Chen Ni, Cai Xinyong, Wang Xingwen, Wu Hao, Chen Zan, Wang Zuowei, Qi Xueling, Lu Dehong, Teng Lianghong, Jian Fengzeng, Wang Leiming
Department of Neurosurgery, Xuanwu Hospital, International Neuroscience Institute, Capital Medical University, #45 Changchun Street, Western District, Beijing, 100053, China.
Department of Pathology, Xuanwu Hospital, Capital Medical University, #45 Changchun Street, Western District, Beijing, 100053, China.
Acta Neuropathol Commun. 2025 Aug 23;13(1):183. doi: 10.1186/s40478-025-02101-0.
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.
H3K27改变的弥漫性中线胶质瘤（DMG）是一种致命疾病，包括四种亚型：H3.3突变型、H3.1/H3.2突变型、EZHIP过表达的H3野生型和EGFR突变型。除H3F3A外，另一个编码组蛋白H3.3的基因H3F3B曾被报道在DMG中发生突变。然而，H3F3B突变型DMG的临床和分子特征尚不清楚。我们回顾性收集了9例H3F3B突变型DMG患者的临床和放射学信息。肿瘤标本进行了DNA甲基化谱分析和二代测序。所有肿瘤均存在体细胞H3F3B p.K27I突变。患者平均年龄为46±6.86岁，6例肿瘤位于脊髓，5例肿瘤累及脑干，2例起源于丘脑。免疫组化显示这些肿瘤表现出H3K27me3表达完全或镶嵌样缺失。对DNA甲基化谱进行无监督的t分布随机邻域嵌入（t-SNE）分析表明，H3F3B突变型DMG形成了一个独特的甲基化簇，与其他H3K27me3缺失的胶质瘤和具有典型组蛋白H3突变的DMG不同。PPM1D和NF1在H3F3B突变型DMG中经常发生突变。生存分析表明，H3F3B突变型DMG的预后与H3K27M突变型DMG相当差。综上所述，H3F3B突变也导致DMG中H3K27三甲基化缺失并导致预后不良。H3F3B突变型DMG与典型H3K27M突变型DMG之间DNA甲基化和突变谱的不同特征可能提示胶质瘤发生的潜在机制不同。
