Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in Glioblastoma

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. ► Multiple receptor tyrosine kinases are amplified in a subset of glioblastoma ► Amplifications of EGFR, MET and PDGFRA are present in intermingled subclones ► Each subclone is functional and actively proliferating ► Subclones share early mutations and are derived from the same precursor