Amplification-Linked Extrachromosomal Mutations in Glioblastoma. Homo sapiens

Alteration of the number of copies of Double Minutes (DMs) with oncogenic EGFR mutations in response to tyrosine kinase inhibitors (TKIs) is a novel adaptive mechanism of glioblastoma. Here we provide evidence that such mutations in DMs, called here Amplification-Linked Extrachromosomal Mutations (ALEMs), originate extrachromosomally and could therefore be completely eliminated from the cancer cells. By exome sequencing of 7 glioblastoma patients we reveal ALEMs in EGFR, PDGFRA and other genes. These mutations together with DMs are lost by cancer cells in culture. We confirm the extrachromosomal origin of such mutations by showing that wild type and mutated DMs may coexist in the same tumor. Analysis of 4198 tumors suggests the presence of ALEMs across different tumor types with the highest prevalence in glioblastomas and low grade gliomas. The extrachromosomal nature of ALEMs explains the observed drastic changes in the amounts of mutated oncogenes (like EGFR or PDGFRA) in glioblastoma in response to environmental changes.

携带致癌性表皮生长因子受体（EGFR）突变的双微体（Double Minutes，DMs）的拷贝数，在响应酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKIs）治疗时发生改变，这是胶质母细胞瘤的一种新型适应性机制。本研究证实，DMs中的此类突变——本文将其命名为扩增相关染色体外突变（Amplification-Linked Extrachromosomal Mutations，ALEMs）——起源于染色体外，因此可被完全从癌细胞中清除。通过对7例胶质母细胞瘤患者的外显子组测序，我们在EGFR、血小板衍生生长因子受体α（PDGFRA）及其他基因中检测到了ALEMs。这类突变与DMs均可在体外培养过程中从癌细胞中丢失。我们通过证实同一肿瘤中可同时存在野生型与突变型DMs，进一步确认了此类突变的染色体外起源。对4198例肿瘤的分析表明，ALEMs广泛存在于多种肿瘤类型中，在胶质母细胞瘤与低级别胶质瘤中检出率最高。ALEMs的染色体外特性，解释了在环境改变时，胶质母细胞瘤中致癌突变基因（如EGFR或PDGFRA）的拷贝数发生剧烈变化的现象。