Evolutionary Trajectories of IDH WT Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis

Cancer Cell. 2019 Apr 15;35(4):692-704.e12. doi: 10.1016/j.ccell.2019.02.007. Epub 2019 Mar 21.

Abstract

We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. TERT promoter mutations often occurred later as a prerequisite for rapid growth. In contrast to this common early path, relapsed tumors acquired no stereotypical pattern of mutations and typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures.

Keywords: cancer evolution; clonal dynamics; glioblastoma; selective advantage; tumor growth; tumor phylogenetics; tumor recurrence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chromosomes, Human, Pair 7
  • DNA Methylation
  • Evolution, Molecular*
  • Gene Expression Regulation, Neoplastic
  • Genetic Heterogeneity
  • Glioblastoma / enzymology
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Mutation*
  • Neoplasm Recurrence, Local
  • Promoter Regions, Genetic
  • Signal Transduction
  • Telomerase / genetics*
  • Telomerase / metabolism
  • Time Factors

Substances

  • Biomarkers, Tumor
  • Isocitrate Dehydrogenase
  • TERT protein, human
  • Telomerase