Histone H3 mutations--a special role for H3.3 in tumorigenesis?

Chromosoma. 2015 Jun;124(2):177-89. doi: 10.1007/s00412-015-0510-4. Epub 2015 Mar 14.

Abstract

Brain tumors are the most common solid tumors in children. Pediatric high-grade glioma (HGG) accounts for ∼8-12 % of these brain tumors and is a devastating disease as 70-90 % of patients die within 2 years of diagnosis. The failure to advance therapy for these children over the last 30 years is largely due to limited knowledge of the molecular basis for these tumors and a lack of disease models. Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78 % of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36 % of non-brainstem gliomas carrying either K27M or G34R/V mutations. Although mutations in many chromatin modifiers have been identified in cancer, this was the first demonstration that histone mutations may be drivers of disease. Subsequent studies have identified high-frequency mutation of histone H3 to K36M in chondroblastomas and to G34W/L in giant cell tumors of bone, which are diseases of adolescents and young adults. Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3. Here, we review the peculiar characteristics of histone H3.3 and use this information as a backdrop to highlight current thinking about how the identified mutations may contribute to disease development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain Stem Neoplasms / diagnosis
  • Brain Stem Neoplasms / genetics*
  • Carcinogenesis / genetics*
  • Child
  • Glioma / diagnosis
  • Glioma / genetics*
  • Histones / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Nucleosomes / genetics
  • Nucleosomes / metabolism

Substances

  • Histones
  • Nucleosomes