From the core to beyond the margin: a genomic picture of glioblastoma intratumor heterogeneity.
From the core to beyond the margin: a genomic picture of glioblastoma intratumor heterogeneity.
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DOI：
10.18632/oncotarget.3297
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Mosser J
中科院分区：
文献类型：
--
作者：
Aubry M;de Tayrac M;Etcheverry A;Clavreul A;Saikali S;Menei P;Mosser J
胶质母细胞瘤（GB）是一种高度侵袭性的原发性脑肿瘤，尽管有积极的治疗，但几乎会系统性复发。其分子生物学的复杂性和异质性是目前治疗GB最具挑战性的问题之一。为了探索这种异质性，我们进行了三个分子水平的全基因组整合筛选：基因组，转录组和甲基化组。我们分析了通过神经导航在10例GB患者的四个不同区域（坏死区、肿瘤区、界面和外周脑区）获得的肿瘤活检。通过主成分分析和加权基因共表达网络分析对样本进行分类，并破译肿瘤内异质性的关键基因标签。在基因组水平上，我们发现了常见的GB拷贝数改变，但有很强的个体间分子异质性。转录组分析突出了一个明显的肿瘤内结构，反映了该研究的手术取样计划，并确定了与癌症标志相关的基因模块。我们提供了与肿瘤内空间梯度高度相关的关键癌症异质性基因的特征，并表明它富含甲基化和表达水平之间相关的基因。我们的研究证实，GB是分子高度多样性，一个单一的肿瘤可以根据其空间结构，窝藏不同的转录GB亚型。
Glioblastoma (GB) is a highly invasive primary brain tumor that almost systematically recurs despite aggressive therapies. One of the most challenging problems in therapy of GB is its extremely complex and heterogeneous molecular biology. To explore this heterogeneity, we performed a genome-wide integrative screening of three molecular levels: genome, transcriptome, and methylome. We analyzed tumor biopsies obtained by neuro-navigation in four distinct areas for 10 GB patients (necrotic zone, tumor zone, interface, and peripheral brain zone). We classified samples and deciphered a key genes signature of intratumor heterogeneity by Principal Component Analysis and Weighted Gene Co-expression Network Analysis. At the genome level, we identified common GB copy number alterations and but a strong interindividual molecular heterogeneity. Transcriptome analysis highlighted a pronounced intratumor architecture reflecting the surgical sampling plan of the study and identified gene modules associated with hallmarks of cancer. We provide a signature of key cancer-heterogeneity genes highly associated with the intratumor spatial gradient and show that it is enriched in genes with correlation between methylation and expression levels. Our study confirms that GBs are molecularly highly diverse and that a single tumor can harbor different transcriptional GB subtypes depending on its spatial architecture.
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