In an international study conducted in Brazil, researchers have identified new glioma subtypes on the basis of epigenetic profile, i.e. how gene expression is modulated. The discovery may help evaluate the prognosis of patients with gliomas and may pave the way for personalized treatment. Gliomas are tumors of the central nervous system.
Houtan Noushmehr, one of the principal investigators for the project and a professor at the Genetics Department of the University of São Paulo's Ribeirão Preto School of Medicine (FMRP-USP), said that epigenetic modifications correspond to a set of chemical processes that shape genome functioning and thus the phenotypic profile, by activating or deactivating genes.
If the genome is comparable to the hardware of a computer, Noushmehr explained, then epigenetics is the software that makes it work.
Among the most widely known epigenetic mechanisms are DNA methylation, the addition of a methyl group (carbon and hydrogen atoms) to the DNA base cytosine, which potentially prevents the expression of some genes, and histone modification, in which acetyl, methyl or other groups are added to or subtracted from the amino acid residues in histones.
The study conducted at FMRP-USP was designed to evaluate DNA methylation profiles in 1,122 adult glioma samples from The Cancer Genome Atlas (TCGA), a joint effort of the US National Cancer Institute and National Human Genome Research Institute, both of which are linked to the National Institutes of Health (NIH). TCGA collects genomic, epigenomic and clinical data as well as tissue samples from cancer patients in many countries.
"We had various kinds of data available for analysis, such as complete tumor genome sequences, complete exome sequences (all the protein-coding genes in genomes), RNA sequencing and DNA methylation data, and chromosome copy number alterations. All these data enabled us to map the epigenetic profiles of tumors. We also had the patients' clinical histories and other details showing how the disease progressed," Noushmehr said.
The analysis was conducted with the aid of bioinformatics tools as part of the postdoctoral research of Tathiane Malta and during the master's research of Thais Sabedot, both under the aegis of a FAPESP Young Investigator project coordinated by Noushmehr.
According to the scientists, until recently, adult gliomas were divided according to their aggressiveness into two main groups: slow-growing tumors (grades 1, 2 and 3) and very aggressive, fast-growing tumors (grade 4).
Previous studies published by Noushmehr in 2010, 2013 and 2015 separately evaluated samples from high- and low-grade tumors and identified tumor subgroups by their DNA methylation profiles.
In this most recent study, samples from high- and low-grade tumors were analyzed together.
"Patients with low-grade tumors typically have a mutation in the IDH1 or IDH2 gene. However, we observed that some low-grade tumors didn't have this mutation, while some high-grade tumors did. We therefore decided to analyze them all together in search of a more accurate classification. Generally speaking, we found that tumors with the IDH1 mutation had a DNA methylation phenotype and a better prognosis," Malta said.
At the end of the analyses, tumors from patients with the IDH1 mutation and 1p/19q chromosome co-deletion, previously considered a homogeneous group, were divided into two new subgroups with different clinical outcomes: G-CIMP-low (low DNA methylation profile and shorter patient survival) and G-CIMP-high (hypermethylation and longer survival).
In the group without the IDH1 mutation, which should have been the most aggressive cases according to previous criteria, the researchers identified a new subgroup with low aggressiveness that displayed similarities with pilocytic astrocytoma, another type of central nervous system tumor that usually has a good prognosis. Survival for patients with this type of tumor was similar to astrocytoma was significantly longer than for patients without the mutation.
"In terms of histopathology, i.e. the microscopic anatomical changes in diseased tissue, these are different tumors, but from the molecular standpoint, they're similar. This finding is very important and will be explored in more detail in future studies," Malta said.
For Noushmehr, the new findings serve to stratify glioma patients more accurately and will contribute to an enhancement of treatment protocols.