title: Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.
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.
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazlollahi
authors.forename: Long P
authors.initials: LP
authors.lastname: Le
authors.forename: Mai
authors.initials: M
authors.lastname: Nitta
authors.forename: Boryana H
authors.initials: BH
authors.lastname: Zhelyazkova
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Davidson
authors.forename: Sara
authors.initials: S
authors.lastname: Akhavanfard
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018740:Genetic Heterogeneity; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020796:Receptor, Platelet-Derived Growth Factor alpha