The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype. Overall design: The GLASS epigenomic cohort consists of 357 DNA methylation samples profiled by either Illumina 450K or EPIC Beadchip methylation arrays. Newly generated DNA methylation data was collected from four different institutions: Henry Ford Hospital (N=103), University of Leeds (UK) (N=8), Chinese University of Hong Kong (N=6), and Luxembourg Institute of Health (N=54) and is available in this series. Previously published data is not included here (they can be accessed at:EGAS00001001255, EGAS00001001854, and EGAS00001001588 .

肿瘤适应或选择被认为是胶质瘤治疗耐药的核心根源。为探究胶质瘤在治疗压力下的纵向表观遗传演化进程，我们对132例配对的初发与复发胶质瘤样本开展了表观基因组分析，这些样本来自异柠檬酸脱氢酶野生型（IDH-wildtype, IDHwt）与异柠檬酸脱氢酶突变型（IDH-mutant, IDHmut）胶质瘤患者。IDHwt胶质瘤的表观基因组随时间保持稳定，整体甲基化水平相对较低；而IDHmut胶质瘤的表观基因组初始呈现全基因组高DNA甲基化水平，随后该水平逐渐降低至与IDHwt肿瘤相近的水平。整合表观基因组学、基因表达谱与功能基因组学分析，我们鉴定出HOXD13是IDHmut星形细胞瘤演化的核心调控因子。此外，IDHmut肿瘤复发时伴随组织学进展，该进展与患者生存相关，这一结论在独立队列中得到了验证。最后，IDHwt与IDHmut肿瘤初始的肿瘤微环境细胞组成存在差异，且经治疗后发生了不同方向的改变：在IDHmut胶质瘤接受治疗后，其新生血管生成与T细胞浸润均有所增加。本研究纳入了目前规模最大的配对纵向胶质瘤样本队列之一，涵盖表观基因组、转录组与基因组测序数据，结果表明IDHmut胶质瘤的治疗与表观基因组向IDHwt样表型的演化相关。整体实验设计：本研究的GLASS表观基因组队列包含357例DNA甲基化样本，这些样本通过Illumina 450K或EPIC微珠芯片甲基化阵列完成检测。本次新生成的DNA甲基化数据来自四家机构：亨利·福特医院（样本量N=103）、英国利兹大学（样本量N=8）、香港中文大学（样本量N=6）以及卢森堡健康研究所（样本量N=54），相关数据已收录于本数据集系列。本数据集未纳入既往已发表的数据，相关数据可通过以下编号获取：EGAS00001001255、EGAS00001001854及EGAS00001001588。