Integrated molecular characterization of IDH-mutant glioblastomas
Integrated molecular characterization of IDH-mutant glioblastomas
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DOI：
10.1111/nan.12523
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发表时间：
2019-02-01
影响因子：
5
通讯作者：
Sahm, F.
中科院分区：
文献类型：
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作者：
Korshunov, A.;Casalini, B.;Sahm, F.
异柠檬酸脱氢酶（IDH）1/2基因突变影响几乎所有WHO分级为II级和III级的星形细胞瘤。IDH突变型星形细胞肿瘤的一个子集进展为IDH突变型胶质母细胞瘤或在首次出现时表现为胶质母细胞瘤的组织学。我们在这里着手评估IDH突变型胶质母细胞瘤的分子谱。方法我们对单中心队列（n = 97）进行了综合分子分析;通过全基因组DNA甲基化分析，拷贝数分析和使用神经肿瘤学定制基因面板的靶向下一代测序进行评估。结果在这97例IDH突变型胶质母细胞瘤中，68例首次出现时为胶质母细胞瘤（“新生”IDH突变型胶质母细胞瘤），29例出现于先前的低级别病变（“进化”IDH突变型胶质母细胞瘤）。DNA甲基化数据的无监督分层聚类揭示IDH突变型胶质母细胞瘤（“新生”和“进化”）形成了与其他弥漫性胶质瘤亚型分开的独特组。发现CDKN 2A/B纯合缺失与较短的生存期相关。结论本研究表明IDH突变型胶质母细胞瘤的DNA甲基化模式与低级别星形细胞瘤不同，但在新生和进化的IDH突变型胶质母细胞瘤中是同质的，并将CDKN 2A鉴定为可能的遗传亚分层的标志物。
Aims Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. Methods We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. Results Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. Conclusions This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.