title: Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypes.
abstract: Glioblastoma (GBM) is known to be a heterogeneous disease; however, the genetic composition of the cells within a given tumour is only poorly explored. In the advent of personalised medicine the understanding of intra-tumoural heterogeneity at the cellular and the genetic level is mandatory to improve treatment and clinical outcome. By combining ploidy-based flow sorting with array-comparative genomic hybridization we show that primary GBMs present as either mono- or polygenomic tumours (64 versus 36%, respectively). Monogenomic tumours were limited to a pseudodiploid tumour clone admixed with normal stromal cells, whereas polygenomic tumours contained multiple tumour clones, yet always including a pseudodiploid population. Interestingly, pseudodiploid and aneuploid fractions carried the same aberrations as defined by identical chromosomal breakpoints, suggesting that evolution towards aneuploidy is a late event in GBM development. Interestingly, while clonal heterogeneity could be recapitulated in spheroid-based xenografts, we find that genetically distinct clones displayed different tumourigenic potential. Moreover, we show that putative cancer stem cell markers including CD133, CD15, A2B5 and CD44 were present on genetically distinct tumour cell populations. These data reveal the clonal heterogeneity of GBMs at the level of DNA content, tumourigenic potential and stem cell marker expression, which is likely to impact glioma progression and treatment response. The combined knowledge of intra-tumour heterogeneity at the genetic, cellular and functional level is crucial to assess treatment responses and to design personalized treatment strategies for primary GBM.
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé (CRP-Santé), 84, Val Fleuri, 1526, Luxembourg, Luxembourg.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.forename: Anna
authors.initials: A
authors.lastname: Golebiewska
authors.forename: Lisa
authors.initials: L
authors.lastname: Evers
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lenkiewicz
authors.forename: Nicolaas H C
authors.initials: NH
authors.lastname: Brons
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nicot
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bougnaud
authors.forename: Frank
authors.initials: F
authors.lastname: Hertel
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barrett
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
mesh_terms: D000818:Animals; D001706:Biopsy; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology*; D056915:DNA Copy Number Variations / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D011003:Ploidies; D012189:Retrospective Studies; D059010:Single-Cell Analysis
chemical_list: D004273:DNA, Neoplasm