PDF(Pubmed)
Abstract：
MYC dysregulation is pivotal in the onset and progression of IDH-mutant gliomas, mostly driven by copy-number alterations, regulatory element alterations, or epigenetic changes. Our pilot analysis uncovered instances of relative MYC overexpression without alterations in the proximal MYC network (PMN), prompting a deeper investigation into potential novel oncogenic mechanisms. Analysing comprehensive genomics profiles of 236 \"IDH-mutant 1p/19q non-co-deleted\" lower-grade gliomas from The Cancer Genome Atlas, we identified somatic genomic alterations within the PMN. In tumours without PMN-alterations but with MYC-overexpression, genes correlated with MYC-overexpression were identified. Our analyses yielded that 86/236 of astrocytomas exhibited no PMN-alterations, a subset of 21/86 displaying relative MYC overexpression. Within this subset, we discovered 42 genes inversely correlated with relative MYC expression, all on 19q. Further analysis pinpointed a minimal common region at 19q13.43, encompassing 15 genes. The inverse correlations of these 15 genes with relative MYC overexpression were re-confirmed using independent scRNAseq data. Further, the micro-deleted astrocytoma subset displayed significantly higher genomic instability compared to WT cases, but lower instability compared to PMN-hit cases. This newly identified 19q micro-deletion represents a potential novel mechanism underlying MYC dysregulation in astrocytomas. Given the prominence of 19q loss in IDH-mutant gliomas, our findings bear significant implications for understanding gliomagenesis.
摘要：
MYC失调在IDH突变神经胶质瘤的发生和进展中至关重要，主要由拷贝数改变驱动，调节元件改变，或表观遗传变化。我们的初步分析发现了相对MYC过表达的实例，而近端MYC网络（PMN）没有改变，促使对潜在的新致癌机制进行更深入的研究。从癌症基因组图谱中分析236“IDH-突变型1p/19q非共缺失”低级别胶质瘤的全面基因组学概况，我们确定了PMN内的体细胞基因组改变。在没有PMN改变但MYC过表达的肿瘤中，鉴定了与MYC过表达相关的基因。我们的分析得出，86/236的星形细胞瘤没有表现出PMN改变，显示相对MYC过表达的21/86的子集。在这个子集内，我们发现42个基因与MYC的相对表达呈负相关,所有在19q进一步的分析在19q13.43确定了一个最小的共同区域，包括15个基因。使用独立的scRNAseq数据重新证实了这15种基因与相对MYC过表达的负相关。Further,与WT病例相比，微缺失星形细胞瘤亚群显示出明显更高的基因组不稳定性，但与PMN命中病例相比，不稳定性较低。这种新发现的19q微缺失代表了星形细胞瘤中MYC失调的潜在新机制。鉴于IDH突变型神经胶质瘤中19q丢失的重要性，我们的发现对于理解胶质细胞生成具有重要意义.
