Genetic Mutations Found Unique to Aggressive Pediatric Gliomas

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(ChemotherapyAdvisor) – Whole-genome sequencing of DNA from seven children with diffuse intrinsic pontine glioma (DIPG) and matched germline tissue and targeted sequencing of an additional 43 DIPGs found 78% of tumors had mutations encoding somatic histone H3 alterations, a study reported in Nature Genetics online January 29.

These results, from the St. Jude Children's Research Hospital — Washington University Pediatric Cancer Genome Project — provide the first evidence showing a specific alteration of histones in cancer. Identification of these mutations may lead to new selective therapeutic targets, since DIPG cannot be treated surgically, said Suzanne Baker, PhD, of St. Jude Children's Research Hospital, and colleagues.

Of the 50 DIPG tumors, 60% had a single alteration in the H3F3A gene that, when translated into a protein, led to the substitution of methionine for lysine as the 27th amino acid in this variant of histone H3 protein. Another 18% carried the same mistake in the HIST1H3B gene. H3F3A and HIST1H3B were found to be mutated in glioblastoma; of 36 such tumors included in this study, 36% carried one of three distinct point mutations, including another single change in H3F3A not found in DIPG.

However, the histone H3 genes were not mutated in any of the 252 other childhood tumors the investigators examined for this study, including low-grade gliomas, medulloblastomas, and ependymomas, and have not been reported in any other cancers, including adult glioblastoma.

DIPG accounts for 10% to 15% of pediatric tumors of the brain and central nervous system and is nearly always fatal.

Abstract

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