Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in Glioblastoma
Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in Glioblastoma
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DOI：
10.1016/j.ccr.2011.11.005
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发表时间：
2011-12-13
期刊：
影响因子：
50.3
通讯作者：
Iafrate, A. John
中科院分区：
文献类型：
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作者：
Snuderl, Matija;Fazlollahi, Ladan;Iafrate, A. John
肿瘤异质性与肿瘤生长和进展以及对治疗的耐药性有关。我们提出了人类恶性脑肿瘤遗传异质性的一个例子，其中多个密切相关的驱动基因在相邻的混合细胞中同时扩增和激活。我们观察到多达三种不同的受体酪氨酸激酶（EGFR、MET、PDGFRA）在不同细胞的单个肿瘤中以相互排斥的方式扩增。每个亚群都在活跃分裂，遗传变化导致蛋白质产生，共存的亚群共享共同的早期基因突变，表明它们源自单个前体细胞。同一肿瘤内不同克隆的稳定共存将对肿瘤对靶向治疗的耐药性具有重要的临床意义。
Tumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.