Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old. Despite the research and clinical trials conducted to identify a possible treatment for DIPG, no effective drug is currently available. These tumors often affect deep midline brain structures in young children, suggesting a connection to early brain development’s epigenetic regulation targets, possibly affecting neural progenitor functions and differentiation. The H3K27M mutation is a known DIPG trigger, but the exact mechanisms beyond epigenetic regulation remain unclear. After thoroughly examining the available literature, we found that over 85% of DIPG tumors contain a somatic missense mutation, K27M, in genes encoding histone H3.3 and H3.1, leading to abnormal gene expression that drives tumor growth and spread. This mutation impacts crucial brain development processes, including the epithelial–mesenchymal transition (EMT) pathway, and may explain differences between H3K27M and non-K27M pediatric gliomas. Effects on stem cells show increased proliferation and disrupted differentiation. The genomic organization of H3 gene family members in the developing brain has revealed variations in their expression patterns. All these observations suggest a need for global efforts to understand developmental origins and potential treatments.
弥漫性内生性桥脑胶质瘤（DIPG），现称为弥漫性中线胶质瘤（DMG），是一种高度侵袭性的儿童恶性肿瘤，主要影响4至9岁的儿童。尽管已开展大量研究和临床试验以探索DIPG的可能治疗方案，目前仍缺乏有效治疗药物。这类肿瘤常累及幼儿脑深部中线结构，提示其发病可能与早期大脑发育表现遗传调控靶点相关，可能影响神经前体细胞功能与分化进程。H3K27M突变是已知的DIPG驱动因素，但除表现遗传调控外的具体作用机制尚未明确。通过系统梳理现有文献，我们发现超过85%的DIPG肿瘤在编码组蛋白H3.3和H3.1的基因中存在K27M体细胞错义突变，该突变导致基因表达异常并驱动肿瘤生长与扩散。此突变影响包括上皮-间质转化（EMT）通路在内的关键脑发育进程，可能解释H3K27M与非K27M儿童胶质瘤的生物学差异。对干细胞的影响表现为增殖增强与分化紊乱。发育期大脑中H3基因家族成员的基因组结构研究揭示了其表达模式的动态变化。这些发现表明，亟需全球协作以深入解析该疾病的发育起源并探索潜在治疗策略。
Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges
肿瘤(癌症)患者之家