NEW YORK (GenomeWeb) – Epigenetic changes might be driving a subset of pediatric brain tumors, according to a new study.
A University of Michigan and University of Southern California-led team of researchers has found that some 80 percent of pediatric posterior fossa ependymomas harbor a global reduction of the H3K27me3 histone modification. As the team reported today in Science Translational Medicine, these tumors exhibited global hypomethylation. As this subset of PF ependymomas was also linked to poorer prognosis, the team suggested that H3K27me3 levels could serve as a biomarker.
"We could do [immunostaining for H3K27me3] very simply, with a very fast and economic process that is easily incorporated in patient care," Michigan's Sriram Venneti said in a statement.
Previous studies of PF ependymomas failed to uncover any recurrent mutations, but as CpGi hypermethylation had been found in the disease, the Michigan-led team examined whether any histone modifications were prevalent.
"Clearly there's more to cancer than just genetic mutations. Not every cancer is going to fit that box of having a genetic driver," Venneti added.
With a combination of mass spectrometry and Western blotting, he and his colleagues analyzed histones they'd extracted from PF ependymomas and supratentorial ependymomas. The PF ependymoma-origin histones showed a substantial reduction in H3K27me3, a finding the researchers confirmed using immunohistochemistry in an additional tumor set. Overall, they found that 82 percent of the pediatric PF ependymomas had a reduction in H3K27me3.
These epigenetic changes were only found in pediatric ependymomas, and not in adult cases, the team further noted. These tumors showed a concurrent increase in H3K27ac, but no differences in other histone modifications. The researchers also reported that PF ependymomas with reduced H3K27me3 also exhibited significant genome-wide hypomethylation with a concomitant increase in gene expression.
This epigenetic pattern, Venneti and his colleagues noted, is similar to what's been seen in another pediatric brain tumor, H3K27M mutant gliomas. The two types also share clinical features such as location and patient age, they added.
"Different mechanisms are involved in these two tumors, but they arrive at the same place," Venneti said. "This suggests low methylation of H3K27me3 is important to tumors in this region of the brain. These tumors arise from similar epigenetic states."
As genomic analyses of PF ependymomas have been unable to uncover genetic differences between those with reduced and non-reduced level of H3K27me3, Venneti and his colleagues suspected that the cause of the low methylation levels was likely not genetic.
Unmethylated CpGis, they noted, have been found to recruit the PRC2 complex, which then acts to increase H3K27me3. In pediatric PF ependymomas, the researchers noted an inverse relationship between H3K27me3 enrichment and CpGi methylation. Because of this, they postulated that CpGi hypermethylation — which has been noted in the disease — might prevent PRC2 from accessing chromatin and lead to low H3K27me3 levels.
This type of ependymoma is also more radiologically and histologically invasive than other PF ependymomas, the researchers reported, adding that it is also associated with a higher rate of incomplete surgical resection and linked to poorer prognosis.
This suggested to the researchers that H3K27me3 immunostaining could be used to gauge prognosis.