Clonal evolution of glioblastoma under therapy

Nat Genet. 2016 Jul;48(7):768-76. doi: 10.1038/ng.3590. Epub 2016 Jun 6.

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to suppression of TGF-β activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM.

MeSH terms

  • Antineoplastic Agents, Alkylating / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Proliferation
  • Clonal Evolution / genetics*
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Latent TGF-beta Binding Proteins / genetics
  • Longitudinal Studies
  • Mutation / genetics*
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology*
  • Survival Rate
  • Temozolomide
  • Transcriptome
  • Transforming Growth Factor beta / genetics
  • Tumor Suppressor Proteins / genetics

Substances

  • Antineoplastic Agents, Alkylating
  • Biomarkers, Tumor
  • LTBP4 protein, human
  • Latent TGF-beta Binding Proteins
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • Dacarbazine
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide