Major finding: Recurrent somatic H3.3 and H3.1 mutations occur specifically in pediatric GBMs.
Mechanism: Covalent histone modifications may be affected by Lys-27 and Gly-34 mutations.
Impact: Cancers driven by regulatory histone mutations may be candidates for epigenetic therapy.
Although pediatric glioblastomas (GBM) are morphologically indistinguishable from adult glioblastomas and have similarly dismal outcomes, mounting evidence suggests that they are distinct molecular entities. Wu and colleagues performed whole-genome and targeted sequencing of pediatric brainstem GBMs, also known as diffuse intrinsic pontine gliomas (DIPG), and nonbrainstem pediatric GBMs. These authors identified mutations in either H3F3A (encoding histone H3.3) or in HIST1H3B (encoding histone H3.1) resulting in an amino acid substitution at Lys-27 or Gly-34 in 78% of DIPGs and 36% of nonbrainstem GBMs. Schwartzentruber and colleagues sequenced the exomes of 48 nonbrainstem pediatric GBMs and identified H3F3A mutations affecting the same residues in 31% of the samples, as well as recurrent loss-of-function mutations in ATRX and DAXX, which encode proteins required for H3.3 recruitment to pericentric heterochromatin and telomeres. The consequences of the H3 mutations remain unclear, though the nonrandom recurrence of the same mutation and the lack of truncating mutations suggest that the alterations affecting Lys-27 and Gly-34 are gain-of-function mutations. Because Lys-27 and Lys-36 are critical sites for posttranslational histone modifications, it is possible that mutations that mimic or disrupt methylation or acetylation at these residues may alter epigenetic regulation of gene expression or global chromatin structure. Consistent with this possibility, Schwartzentruber and colleagues observed distinct expression patterns and aberrant telomere elongation in histone H3 Lys-27– and Gly-34–mutant tumors. Histone H3 mutations seem to occur exclusively in GBM and are far more prevalent in the high-grade pediatric gliomas, suggesting that an altered chromatin landscape may specifically confer a selective growth advantage in the developing brain and that epigenetic therapies may be particularly effective in the pediatric setting.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.
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