Genetic Evolution of Glioblastoma Stem-Like Cells From Primary to Recurrent Tumor

Francesca Orzan, Francesca De Bacco, Giovanni Crisafulli, Serena Pellegatta, Benedetta Mussolin, Giulia Siravegna, Antonio D'Ambrosio, Paolo M. Comoglio, Gaetano Finocchiaro, Carla Boccaccio

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Glioblastoma (GBM) is a lethal tumor that displays remarkable genetic heterogeneity. It is also known that GBM contains a cell hierarchy driven by GBM stem-like cells (GSCs), responsible for tumor generation, therapeutic resistance, and relapse. An important and still open issue is whether phylogenetically related GSCs can be found in matched primary and recurrent GBMs, and reflect tumor genetic evolution under therapeutic pressure. To address this, we analyzed the mutational profile of GSCs isolated from either human primary GBMs (primary GSCs) or their matched tumors recurring after surgery and chemoradiotherapy (recurrent GSCs). We found that recurrent GSCs can accumulate temozolomide-related mutations over primary GSCs, following both linear and branched patterns. In the latter case, primary and recurrent GSCs share a common set of lesions, but also harbor distinctive mutations indicating that primary and recurrent GSCs derive from a putative common ancestor GSC by divergent genetic evolution. Interestingly, TP53 mutations distinctive of recurrent GSCs were detectable at low frequency in the corresponding primary tumors and likely marked pre-existent subclones that evolved under therapeutic pressure and expanded in the relapsing tumor. Consistently, recurrent GSCs displayed in vitro greater therapeutic resistance than primary GSCs. Overall, these data indicate that (a) phylogenetically related GSCs are found in matched primary and recurrent GBMs and (b) recurrent GSCs likely pre-exist in the untreated primary tumor and are both mutagenized and positively selected by chemoradiotherapy. Stem Cells 2017;35:2218–2228.

Original languageEnglish
Pages (from-to)2218-2228
Number of pages11
JournalStem Cells
Volume35
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Molecular Evolution
Glioblastoma
Stem Cells
Neoplasms
temozolomide
Chemoradiotherapy
Mutation
Pressure
Genetic Heterogeneity
Therapeutics

Keywords

  • Genetic evolution
  • Glioblastoma stem-like cells
  • Primary glioblastoma
  • Recurrent glioblastoma
  • Temozolomide
  • Therapeutic pressure

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Genetic Evolution of Glioblastoma Stem-Like Cells From Primary to Recurrent Tumor. / Orzan, Francesca; De Bacco, Francesca; Crisafulli, Giovanni; Pellegatta, Serena; Mussolin, Benedetta; Siravegna, Giulia; D'Ambrosio, Antonio; Comoglio, Paolo M.; Finocchiaro, Gaetano; Boccaccio, Carla.

In: Stem Cells, Vol. 35, No. 11, 01.11.2017, p. 2218-2228.

Research output: Contribution to journalArticle

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