Cell Reports (Apr 2018)

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

  • Camila Ferreira de Souza,
  • Thais S. Sabedot,
  • Tathiane M. Malta,
  • Lindsay Stetson,
  • Olena Morozova,
  • Artem Sokolov,
  • Peter W. Laird,
  • Maciej Wiznerowicz,
  • Antonio Iavarone,
  • James Snyder,
  • Ana deCarvalho,
  • Zachary Sanborn,
  • Kerrie L. McDonald,
  • William A. Friedman,
  • Daniela Tirapelli,
  • Laila Poisson,
  • Tom Mikkelsen,
  • Carlos G. Carlotti, Jr.,
  • Steven Kalkanis,
  • Jean Zenklusen,
  • Sofie R. Salama,
  • Jill S. Barnholtz-Sloan,
  • Houtan Noushmehr

Journal volume & issue
Vol. 23, no. 2
pp. 637 – 651

Abstract

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Summary: Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression. : IDH-mutant lower-grade glioma glioblastoma often progresses to a more aggressive phenotype upon recurrence. de Souza et al. examines the intra-subtype heterogeneity of initial G-CIMP-high and use this information to identify predictive biomarkers for assessing the risk of recurrence and malignant transformation. Keywords: longitudinal gliomas, DNA methylation, IDH mutation, G-CIMP-high, intra-subtype heterogeneity, malignant transformation and recurrence, G-CIMP-low, stem cell-like glioblastoma, predictive biomarkers