Research
SUMMARY OF ACQUIRED GENETIC AND CELL-STATE CHANGES IN IDH-MUTANT GLIOMA PROGRESSION
Johnson, Kevin C., Avishay Spitzer, Frederick S. Varn, et al. ‘Acquired Genetic and Cell-State Changes in IDH-Mutant Glioma Progression’. Nature, 3 June 2026, 1–12.
Following is a summary of an article kindly completed by Piotr Skubis, molecular bioengineering student at Imperial College London, which appeared in “Nature” in June 2026.
Background
Tumours are composed of cells, which have either acquired changes in their DNA (genetic changes) or in the way their genes are activated (epigenetic changes). These two types of alterations are what causes the cells to be malignant, to multiply, and to resist treatment.
The cells we find within each tumour are not identical: the changes they have acquired differ from one cell to another. Advancements in technology over the last 20 years have allowed us to read the nucleic acid (DNA and RNA) sequences in each cell originating from a tumour surgically removed from a patient, which allows us to identify the cells in tumours, to better understand which cells cause progression and aggressiveness, relapse, or drug resistance.
In low grade glioma, the difficulty of treatment stems from progression to more aggressive, high-grade tumours, which occurs in most cases. To better understand what genetic and epigenetic changes might drive this progression and cause relapses, Johnson et al. have analysed the cells from low-grade, IDH mutant tumours, when they are first diagnosed, and after they have progressed.
Heterogeneity
Within the malignant cells present in the tumours, the authors have identified five major groups:
1. Oligodendrocyte / Oligodendrocyte Precursor Cell-like state,
2. Astrocyte-like state,
3. Mesenchymal-like state,
4. Cycling state,
5. Undifferentiated state.
These five groups of cells co-exist in a tumour, illustrating the principle of heterogeneity: the fact that not all cells within a tumour are identical.
The first three states resemble cells that are found in the healthy tissue:
1. Oligodendrocytes insulate neural connections, making it possible to send electrical impulses very quickly. Precursor cells are “immature” cells, which develop into oligodendrocytes.
2. Astrocytes support brain cells by providing nutrients, regulating what can enter the brain from the blood, and removing waste products.
3. Mesenchymal tissue is a type of embryonic tissue, which develops into various tissues, including the nervous system.
It is common for tumour cells to activate cellular programs that, under healthy development, are necessary to build tissue. These programs cause the tumour cells to multiply (divide) rapidly, as do healthy cells during normal development.
The “cycling” group is composed of cells which are undergoing multiplication, and the “undifferentiated” group resembles cells which have not “committed” to specialise and become a specific cell type: like how foetal cells, which will develop into all the organs, don’t “commit” until later in the embryonic development.
The same states were identified in both oligodendrogliomas and astrocytomas, and some were previously identified in more aggressive, IDH-wildtype tumours.
Changes at recurrence
The authors have found that at recurrence, the fraction of malignant cells in the astrocyte-like state decreases, and more cells are in the undifferentiated, cycling and Mesenchymal-like states. Both genetic and epigenetic changes contributed to this shift.
This likely means that recurrence is caused by mutations occurring after the primary tumour is surgically removed, and that the less differentiated (“uncommitted”) population is driving the progression.
Importantly, it was found that in oligodendroglioma, the changes (hypermutation) caused by alkylating chemotherapy (e.g, Temozolomide) were associated with a higher fraction of undifferentiated states and lower fraction of Astrocyte-like states.
Because of this finding, it is possible that this chemotherapy regimen might play a role in recurrence: a better therapy would decrease the fraction of undifferentiated cells.
Immune cells of the brain
The Mesenchymal-like state, which was found to be more prevalent at recurrence, was not associated with genetic changes. The authors suggest that the interactions with other cells present in the brain contributed to the higher number of these cells, and to address this question, the immune cells of the brain (myeloid cells) were analysed.
The two key immune cell types were microglia and macrophages. The former are resident immune cells of the brain, which are present in brain tumours in high numbers. The latter originate in the bone marrow and invade the brain in diseased states.
At recurrence, there were more macrophages and less microglia. This change was increased in patients who underwent radiotherapy treatment, and the authors suggest that this therapy type influences inflammation, which affects malignant cell states and treatment response.
An inflammatory environment, associated with higher number of macrophages, coincided with a higher fraction of Mesenchymal-like cells in the malignant population. Higher numbers of Mesenchymal-like cells, which multiply quickly, were associated with reduced overall survival in both astrocytoma and oligodendroglioma.
Conclusion
The authors have examined the cells that constitute the low-grade glioma tumours, at first occurrence and at recurrence. The progression was found to be driven by changes in genetics and the microenvironment, particularly the immune cells.
Therapeutic resistance is understood to be associated with genetic differences, including ones caused by treatment—alkylating chemotherapy leading to hypermutation, and radiotherapy leading to an inflammatory environment. While these treatments provide survival benefits, they might impact recurrence and resistance.
The authors have identified the cell states that are particularly associated with progression, and which ideally should be targeted by the therapeutic regimen, leading to more long-term benefits. Mutant IDH inhibitors have been suggested as one such method.
This study improves our understanding of IDH-mutant glioma, its evolution, heterogeneity in the cells that constitute the tumours, and the factors leading to disease progression.
Piotr Skubis,
MEng in Molecular Bioengineering