弥漫性胶质瘤是一类异质性的原发性中枢神经系统肿瘤。由于其浸润性生长使完全手术切除成为不可能，大多数高级别弥漫性胶质瘤采用辅助化疗和放射治疗。复发/进展的弥漫性胶质瘤与原发瘤相比可能显示遗传差异，揭示了其分子演化和治疗抵抗机制。成人型有或无异柠檬酸脱氢酶基因突变的弥漫性胶质瘤，肿瘤复发/进展可能与编码DNA错配修复蛋白的基因突变有关，导致肿瘤突变负荷显著增加。这一现象与DNA烷化剂替莫唑胺的治疗密切相关，后者是成人弥漫性胶质瘤化疗管理的基石。在复发高级别胶质瘤的儿科患者中，后期治疗DNA错配修复缺陷和获得的高肿瘤突变负荷的研究相对较少。在这里，我们报告一个机构的小型研究，其中包括十一个儿科患者，其初始高级别星形胶质瘤样本及其复发样本之间经过替莫唑胺的治疗。我们确定了三个复发时具有增加的肿瘤突变负荷的案例，其中包括两个弥漫性半球胶质瘤H3 G34突变（其中一个是先前报告的）。我们还表明，通过下一代DNA测序和基于DNA甲基化的分析，基于2021年世界卫生组织标准得出了10个案例（91%）的综合诊断。我们的发现表明，治疗后复发时的增加的肿瘤突变负荷在儿科型高级别弥漫性胶质瘤中具有相关性。弥漫性半球胶质瘤H3 G34突变可能特别容易发生这种现象。©2023 BioMed Central Ltd., part of Springer Nature.

Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.© 2023. BioMed Central Ltd., part of Springer Nature.