Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas.
Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas.
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DOI：
10.1093/neuonc/now231
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发表时间：
2017-04-01
期刊：
影响因子：
15.9
通讯作者：
Klink B
中科院分区：
文献类型：
--
作者：
Abou-El-Ardat K;Seifert M;Becker K;Eisenreich S;Lehmann M;Hackmann K;Rump A;Meijer G;Carvalho B;Temme A;Schackert G;Schröck E;Krex D;Klink B
原发性胶质母细胞瘤（GBM）的进化尚不清楚。多灶性GBM（即在一名患者中出现多个同步病变）可以阐明GBM的发展。我们采用阵列- cgh、谱核型、基因表达阵列和下一代测序技术对6例患者的12个GBM病灶进行了首次综合研究。多灶性GBMs在基因上与原发性GBMs相似。比较同一患者的疫源地证实了它们的单克隆来源。所有肿瘤都有3个GBM核心通路的改变：RTK/PI3K、p53和RB调控通路，所有（100%）患者的EGFR和CDKN2A/B发生畸变。这种意想不到的高频率反映了多灶性GBMs的独特遗传特征，并可能解释其高度恶性和侵袭性表型。令人惊讶的是，这些基因/通路的突变类型在同一患者的肿瘤病灶中是不同的。例如，我们在PTEN、TP53、EGFR和CDKN2A/B中发现了不同的突变/畸变，因此这些突变/畸变一定是在肿瘤发展的后期独立发生的。我们还发现，染色体断裂是一种晚期事件，发生在具有野生型TP53的肿瘤中。在所有患者中只有2个事件被发现是早期的：PTEN单拷贝丢失和TERT启动子点突变。多灶性GBMs是通过平行遗传进化形成的。3个主要通路的高频率改变表明这些是GBM进化的重要步骤；然而，它们的晚发生表明它们不是创始事件，而是亚克隆驱动因素。这可能解释了原发性GBM中明显的遗传异质性，因此对GBM治疗具有重要意义。
The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development. We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing. Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations. Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy.