Genetic and Epigenetic Features of Rapidly Progressing IDH-Mutant Astrocytomas
Genetic and Epigenetic Features of Rapidly Progressing IDH-Mutant Astrocytomas
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DOI：
10.1093/jnen/nly026
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发表时间：
2018-07-01
影响因子：
3.2
通讯作者：
Hatanpaa, Kimmo J.
中科院分区：
文献类型：
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作者：
Richardson, Timothy E.;Sathe, Adwait Amod;Hatanpaa, Kimmo J.
IDH突变型星形细胞瘤的侵袭性明显低于IDH野生型星形细胞瘤。我们分析了癌症基因组图谱数据集（TCGA），并确定了一小群IDH突变型WHO II-III级星形细胞瘤（n = 14），其预后意外不良，其特征是在初次诊断后3年内迅速进展为胶质母细胞瘤和死亡。与年龄相似的对照组患者中具有典型的、延长的无进展生存期的IDH突变型肿瘤相比，快速进展组中的肿瘤的特征是总体拷贝数改变水平显著增加（[CNA]; p = 0.006）。相反，突变负荷是相似的，甲基化模式也是如此，与IDH突变型星形细胞瘤一致。快速进展IDH突变组中的两个胶质瘤（14%），但TCGA中的其他II-III级胶质瘤（n = 283）均不存在与维持染色体稳定性相关的基因（FANCB和APC）致病突变。这些结果表明，染色体不稳定性可以否定IDH突变在WHO II-III型星形细胞瘤中的有益作用。CNA增加的机制尚不清楚，但在某些情况下似乎是由于染色体稳定性基因突变所致。增加的CNA可以作为肿瘤快速进展风险的生物标志物。
IDH-mutant astrocytomas are significantly less aggressive than their IDH-wildtype counterparts. We analyzed The Cancer Genome Atlas dataset (TCGA) and identified a small group of IDH-mutant, WHO grade II-III astrocytomas (n = 14) with an unexpectedly poor prognosis characterized by a rapid progression to glioblastoma and death within 3 years of the initial diagnosis. Compared with IDH-mutant tumors with the typical, extended progression-free survival in a control group of age-similar patients, the tumors in the rapidly progressing group were characterized by a markedly increased level of overall copy number alterations ([CNA]; p = 0.006). In contrast, the mutation load was similar, as was the methylation pattern, being consistent with IDH-mutant astrocytoma. Two of the gliomas (14%) in the rapidly progressing, IDH-mutant group but none of the other grade II-III gliomas in the TCGA (n = 283) had pathogenic mutations in genes (FANCB and APC) associated with maintaining chromosomal stability. These results suggest that chromosomal instability can negate the beneficial effect of IDH mutations in WHO II-III astrocytomas. The mechanism of the increased CNA is unknown but in some cases appears to be due to mutations in genes with a role in chromosomal stability. Increased CNA could serve as a biomarker for tumors at risk for rapid progression.