A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas

Sriram Venneti, Mariarita Santi, Michelle Madden Felicella, Dmitry Yarilin, Joanna J. Phillips, Lisa M. Sullivan, Daniel Martinez, Arie Perry, Peter W. Lewis, Craig B. Thompson, Alexander R. Judkins

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM.

Original languageEnglish (US)
Pages (from-to)743-753
Number of pages11
JournalActa Neuropathologica
Volume128
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Diagnostic biomarker
  • Epigenetics
  • H3F3A mutation
  • H3K27me3
  • K27M mutation
  • Methylation
  • Pediatric glioblastoma
  • Prognosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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