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Sequencing Studies Implicate Chromatin-Related Genes in Childhood Brain Cancers

NEW YORK (GenomeWeb News) – A pair of studies published online this weekend point to histone and chromatin remodeling genes as culprits in a subset of brain cancers occurring in children and young adults.

The first, a study by an international team led by investigators at McGill University who did exome sequencing on tumor samples from four dozen children with glioblastoma, found that mutations in the histone gene H3F3A and the chromatin remodeling-related genes ATRX and DAXX were recurrent in a substantial proportion of these cases. The researchers reported their findings in Nature.

"This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans," co-corresponding author Nada Jabado, a human genetics, experimental medicine, and pediatrics researcher at McGill University, and colleagues wrote, "and our data suggest that defects of the chromatin architecture underlie pediatric and young adult GBM pathogenesis."

In an effort to learn more about the genetics of GBM in children, Jabado and her colleagues captured coding regions of the genome from 48 pediatric GBM samples using Illumina's TruSeq kit. They then sequenced these regions to a median of 61 times coverage by paired-end sequencing on the Illumina HiSeq 2000.

The exomes of matched normal samples were also sequenced for six of the children and comparisons between tumor and normal genomes in these individuals were used to help prioritize candidate mutations for the other tumors as well.

Analyses of the exomes pointed to recurrent mutations to three genes involved in histone or chromatin-related process: the histone H3.3 coding gene H3F3A and the chromatin remodeling pathway genes ATRX and DAXX, which code for components of a complex contributing to the proper placement of histone H3.3 proteins.

Between them, the three genes were mutated in 21 of the 48 tumor exomes, researchers found. Moreover, 31 percent of the childhood GBM exomes specifically contained alterations to H3F3A that led to substitutions at either amino acid 27 or amino acid 34 of the resulting protein, both well-conserved sites in the histone's tail region.

Along with these alterations, researchers also saw mutations affecting the tumor suppressor gene TP53 in more than half of the childhood GBM tumors tested overall and in 86 percent of tumors with H3F3A or ATRX mutations.

Moreover, they noted, the tumors harboring mutations in TP53, H3F3A, and ATRX-DAXX complex genes appeared especially prone to shifts in gene expression and telomere length patterns.

Despite the recurrence of H3F3A in the pediatric GBM exomes, though, the team did not find the same mutations in non-GBM samples when they screened 784 more brain cancer samples. The mutations were also far more common in tumors from children and young adults than from adults with GBM.

An independent group representing the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project found similar changes to H3F3A — and a related histone gene HISTH3B — when they sequenced matched tumor-normal samples from seven children with a brainstem cancer called pediatric diffuse intrinsic pontine glioma, which usually has GBM-like histopathology.

As they reported in Nature Genetics, that team initially did whole-genome sequencing on seven tumor-normal pairs and then used findings from the tumor genomes to guide targeted Sanger sequencing studies on another 69 DIPG or non-brainstem localized pediatric GBM cases.

Their results suggest that recurrent amino acid 27-affecting mutations can be found in both the H3F3A gene and in HISTH3B, which codes for the histone H3.1 isoform. These mutations turned up in the majority of pediatric DIPGs: almost 80 percent of the DIPG tumors tested by whole-genome or targeted sequencing contained mutations to the amino acid 27 codon. And just over one-fifth of the non-brainstem pediatric GBM tumors contained the mutations that would alter the amino acid 27 sites of the H3.1 or H3.3 histone isoforms.

In 14 percent of the non-brainstem GBM cases, researchers saw recurrent mutations in the H3F3A gene that cause substitutions at amino acid 34 of the H3.3 histone — another of the recurrent mutations detected in childhood GBM exomes by the McGill-led group.

On the other hand, the amino acid 34 codon mutation did not turn up in any of the DIPG samples tested by the St. Jude-Washington University team. Nor did researchers find recurrent mutations in any of the other histone H3 isoform genes tested in the pediatric brain cancers, hinting that histones H3.1 and H3.3 may share transcriptional or post-translational features that are especially pertinent to the biology of DIPG and non-brainstem GBM tumors in children.

"Given the complex regulatory roles of histone H3, these mutations could potentially affect epigenetic regulation of gene expression, selective regulation of developmental genes, or telomere length or stability," the study's authors noted.