Researchers Are Studying the Origin of Glioma

Over the past decade, scientists have improved their understanding of the origin of gliomas through epidemiologic research, molecular profiling and studies of genetically engineered mice. In Seminars in Neurology, Neurosurgeon Daniel Cahill, MD, PhD, of Massachusetts General Hospital, and Sevin Turcan, PhD, of Heidelberg University Hospital, summarize these advances and their relevance to the search for glioma therapeutic targets and biomarkers.

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Glioma has proven to be a molecularly heterogeneous disease, Drs. Cahill and Turcan explain. Most low-grade gliomas and secondary glioblastomas have recurrent mutations in the isocitrate dehydrogenase (IDH) gene family, IDH1 and IDH2. Genome-wide analyses have demonstrated three molecular subclasses of low-grade gliomas, based in large part on their IDH status: mutated, in astrocytomas or oligodendrogliomas, or normal (wild type). Given this heterogeneity, the authors note that there may be more than one cell of origin for gliomas. Alternatively, the different molecular subtypes may reflect distinct molecular states influenced by developmental age.

Efforts to identify environmental and heritable genetic risk factors for glioma are well underway. So far, the only well-established environmental risk factor is high-dose ionizing radiation. Complicating matters further, glioblastomas that lack IDH mutations have complex alterations in their genomes and a particularly high frequency of somatic mutation. Still, researchers have identified 26 single-nucleotide polymorphisms that influence glioma risk. Another example of the intriguing findings coming from genome-wide profiling is that 80% to 90% of IDH wild-type gliomas show chromosome 7 gain and chromosome 10 loss, and these events have been identified as early drivers of tumor pathogenesis.

Studies in genetically engineered mice suggest that multiple cell types in the central nervous system are susceptible to glioma-specific gene mutations, either alone or in combination. As such, these different cell types might differ in their likelihood of transformation. Of course, caution is needed in interpretation of these studies, since glioma progenitor cells might differ between mice and humans.

In a study that relied on single-cell sequencing of human samples led by Mario Suva, MD, PhD, assistant professor of pathology at Mass General Cancer Center, primary IDH-mutant gliomas had evidence of a shared common progenitor, regardless of their molecular subclassification. Most of the transcriptional differences between the subtypes were explained by genetic differences and the composition of the tumor microenvironment, not by distinct cell of origin. The authors speculate that genetic alterations of IDH-mutant cells may create different microenvironments that lead to distinct clinical courses. Identification of the progenitor or origin cell for gliomas could offer an Achilles' heel to target for better treatments of these tumors.

A key future step in research will be to use genetically engineered mouse models for drug screening. Along with Isabel Arrillaga-Romany, MD, PhD, associate clinical director, Neuro-Oncology at the Mass General Cancer Center, Dr. Cahill and Dr. Turcan have recently been awarded a grant from the private foundation Oligo Nation to study treatments for IDH-mutant oligodendroglioma.

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