胶质母细胞瘤中多种受体酪氨酸激酶基因的镶嵌扩增。

Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.

机构信息

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

出版信息

Cancer Cell. 2011 Dec 13;20(6):810-7. doi: 10.1016/j.ccr.2011.11.005. Epub 2011 Dec 1.

DOI:10.1016/j.ccr.2011.11.005

Abstract

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.

摘要

肿瘤异质性与肿瘤的生长和进展以及对治疗的抵抗有关。我们提出了一个人类恶性脑肿瘤中遗传异质性的例子，其中多个密切相关的驱动基因在相邻混合细胞中同时被扩增和激活。我们观察到多达三种不同的受体酪氨酸激酶（EGFR、MET、PDGFRA）在单个肿瘤的不同细胞中以相互排斥的方式扩增。每个亚群都在积极分裂，遗传变化导致蛋白质产生，共存的亚群共享共同的早期遗传突变，表明它们来自单个前体细胞。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产生重要的临床意义。