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Two Glioma Subtypes Share the Same Lineage

NEW YORK (GenomeWeb) – Two brain glioma subtypes may originate from the same progenitor cells, according to a new sequencing study.

Researchers from Massachusetts General Hospital and elsewhere combined bulk tumor and single-cell RNA sequencing to tease out the influences of genotype and tumor microenvironment on glioma subtypes. As they reported today in Science, they examined nearly 10,000 single-cell RNA-seq profiles from 10 IDH-A gliomas, more than 4,000 single-cell RNA-seq profiles from six IDH-O gliomas, and bulk glioma RNA-sequencing data from the Cancer Genome Atlas.

They found that differences between IDH-A and IDH-O gliomas — two major subtypes of the disease — are largely explained by differences in genetic mutations and tumor environment, rather than by glial lineage.

"Our study redefines the cellular composition of two closely related gliomas characterized by mutations in the IDH gene — astrocytomas and oligodendrogliomas," co-senior author Mario Suvà at MGH said in a statement. "While we know these are genetically distinct tumor types, we did not know whether they had similar cells of origin or if their expression differences could be explained by genetics, by the cells from which they developed, or by the tumor microenvironment."

Using the bulk and single-cell RNA-seq data, he and his colleagues compared the expression profiles of IDH-A and IDH-O gliomas. They first teased out malignant cells or non-malignant cells based on their gene expression and copy-number variation profiles.

In the bulk tumors, the researchers noted that about 550 genes were differentially expressed between IDH-A and IDH-O gliomas, but when they examined the expression profiles of malignant IDH-A and malignant IDH-O glioma cells, only half those genes were differentially expressed. This suggested to the researchers that differences in the tumor microenvironment might account for the rest.

Within malignant IDH-A and IDH-O glioma cells, the researchers found that genetic alterations affected differences in expression between the subtypes. For instance, they reported that malignant IDH-A glioma cells expressed high levels of genes located on chromosomes 1p and 19q, which were deleted in the IDH-O gliomas.

Together, they said this indicates that both the tumor microenvironment and genetic changes are reflected within bulk TCGA expression signatures for glioma.

IDH-A gliomas are thought to stem from astrocytic glial lineages, while IDH-O gliomas are suspected to be from the oligodendrocytic glial lineage, but both also contain markers the other cell types. The researchers noted that as genetic changes and tumor microenvironment accounted for most differences between IDH-A and IDH-O, they suggested that the two glioma subtypes might arise from the same cellular lineage.

Through a principal components analysis, analysis of genes differentially expressed in IDH-A and IDH-O, and examination of methylation patterns, the researchers concluded that the two subtypes likely had a shared histogenesis. In particular, they found that undifferentiated glioma cells from IDH-A and IDH-O tumors had highly similar gene expression profiles that were associated with proliferation and stemness.

"We were surprised to find that cancer cells from these two tumor subtypes share similar stem cell programs and glial lineages of differentiation," Suvà said.

Both types of IDH gliomas, he and his colleagues reported, are composed of non-proliferating differentiated cells from the two glial lineages as well as proliferating undifferentiated cells. Higher-grade tumors, they noted, had a higher portion of proliferating cells.

"Additionally, we observed that cancer cells that become more differentiated do not proliferate, even in more advanced tumors," Suvà added. "That suggests that pushing cells towards differentiation — something we currently do not know how to do in patients — could significantly halt tumor growth. As these tumors share stem cell programs that drive their growth, an alternative approach could be to target specific cell types with immunotherapies."