The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen
The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen
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DOI：
10.1101/2021.08.09.455687
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
T. Malta;Thais S Sabedot;I. Datta;L. Garofano;W. Vallentgoed;F. Varn;Kenneth Aldape;F. D’Angelo
中科院分区：
文献类型：
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作者：
T. Malta;Thais S Sabedot;I. Datta;L. Garofano;W. Vallentgoed;F. Varn;Kenneth Aldape;F. D’Angelo
肿瘤适应或选择被认为是胶质瘤治疗抵抗的基础。为了研究神经胶质瘤对治疗压力的纵向表观遗传学演变，我们对143例匹配的IDH野生型（IDHwt）和IDH突变型（IDHmut）神经胶质瘤的初始和复发患者进行了表观基因组分析。IDHwt胶质瘤显示纵向稳定的表观基因组，具有相对低水平的整体甲基化，而IDHmut胶质瘤的表观基因组显示初始高水平的全基因组DNA甲基化，其逐渐降低至与IDHwt肿瘤相似的水平。通过整合DNA甲基化和基因表达数据，在IDHmut复发性肿瘤中观察到细胞周期和分化的假定主调节因子的适应性变化。此外，IDHmut肿瘤的复发伴随着组织学进展，这反过来影响了生存率，如在独立队列中验证的。最后，肿瘤微环境的初始细胞组成在IDHwt和IDHmut肿瘤之间不同，并且在治疗后发生差异性变化，表明在治疗IDHmut胶质瘤后增加的新血管生成和T细胞浸润。我们的研究提供了用表观基因组学、转录组学和基因组学分析的配对胶质瘤样本的最大队列之一;我们的结果表明，IDHmut胶质瘤的治疗将表观基因组重塑为IDHwt样表型。因此，可能需要重新审视该患者人群中早期遗传毒性治疗的普遍做法。
Tumor adaptation or selection is thought to underlie therapy resistance of gliomas. To investigate the longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 143 matched initial and recurrent patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) gliomas. IDHwt gliomas showed a longitudinally stable epigenome with relatively low levels of global methylation, whereas the epigenome of IDHmut gliomas showed initial high levels genome-wide of DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. By integrating DNA methylation and gene expression data, adaptive changes of putative master regulators of the cell cycle and of differentiation were seen in IDHmut recurrent tumors. Furthermore, relapses of IDHmut tumors were accompanied by histological progression which in turn influenced survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment differed between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment for IDHmut gliomas. Our study provides one of the largest cohorts of paired glioma samples profiled with epigenomics, transcriptomics and genomics; and our results demonstrate that the treatment of IDHmut gliomas reshapes the epigenome towards an IDHwt-like phenotype. Accordingly, the prevalent practice of early genotoxic treatment in this patient population may need to be revisited.