Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns
Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns
复制标题
DOI：
10.1007/s00401-020-02209-8
复制
发表时间：
2020-09-08
影响因子：
12.7
通讯作者：
Tabori, Uri
中科院分区：
文献类型：
--
作者：
Dodgshun, Andrew J.;Fukuoka, Kohei;Tabori, Uri
导致超突变的复制修复缺陷（RRD）是高级胶质瘤（HGG）的一个重要驱动机制，主要发生在RRD相关基因的种系突变的背景下。虽然HGG呈现对应于致癌突变的DNA甲基化的特定模式，但这在复制修复缺陷型肿瘤中尚未得到充分研究。我们利用450 k或850 k甲基化阵列分析了RRD基因突变背景下产生的51个HGG。将这些与未知来自RRD患者的HGG进行比较。在胶质瘤基因如IDH 1和H3 F3 A中含有继发突变的RRD HGG显示了与这些甲基化亚组相对应的甲基化模式。引人注目的是，缺乏这些已知的二级突变的RRD HGG与先前标记为“野生型-C”或“儿科RTK 1”的不完全描述的HGG组聚集在一起。两个比较HGG队列的独立分析显示，其他RRD/超突变肿瘤在这些亚组中聚集，表明未诊断的RRD可能导致该位置的一些HGG聚集。与其他癌症中描述的CpG岛甲基化表型相比，RRD HGG显示出独特的CpG岛去甲基化表型。低甲基化在基因启动子处富集，在对细胞存活至关重要的基因和途径（包括细胞周期、基因表达、细胞代谢和组织）中具有显著的去甲基化。这些数据表明，甲基化阵列可以为RRD HGG的检测提供诊断信息。此外，我们的研究结果强调了这些高度失调的超突变癌症中独特的自然选择压力，并提供了超突变和RRD对癌症表观基因组的新影响。
Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such asIDH1andH3F3Adisplayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.