Where Does Brain Cancer Begin? A Mystery Finally Revealed

This study shows that gliomas with mutations in the IDH gene likely begin in immature brain cells called glial progenitor cells, especially those that give rise to oligodendrocytes. These cells can carry the initial mutation for a long time without forming a visible tumor. With the accumulation of new mutations, they begin to multiply uncontrollably and evolve into brain cancer. Identifying this cell of origin helps to understand how these tumors develop and may pave the way for earlier diagnoses and new treatment strategies.

Gliomas with mutations in the gene called isocitrate dehydrogenase, known as the IDH gene, are the most common type of malignant brain tumor in young adults, especially in people under fifty years old. These tumors arise from the brain's supporting cells, called glial cells.

Although it has been known for some time that the mutation in the IDH gene occurs very early in tumor development, scientists had not yet been able to identify exactly which type of brain cell undergoes this initial mutation and gives rise to the cancer. This initial cell is called the "cell of origin."

Previous studies have shown that there are two main subtypes of these IDH-mutated gliomas: oligodendroglioma and astrocytoma. Despite presenting clinical and genetic differences, detailed gene function analyses have indicated that both share similar characteristics, suggesting they may originate from the same type of precursor cell.

Because immature cells tend to divide more frequently, they have a greater chance of accumulating genetic errors. Therefore, neural stem cells and glial progenitor cells have always been considered strong candidates to be the cell of origin for these tumors.

The main objective of this study was to discover exactly where and in what type of cell the initial mutation of the IDH gene arises. To do this, the researchers used extremely sensitive genetic analysis techniques, capable of detecting mutations even when they are present in very few cells.

Brain tissue samples from seventy patients were analyzed, including tumor tissue, regions near the tumor, deep brain areas known as the subventricular zone, and blood samples. Importantly, the brain regions analyzed outside the tumor were carefully selected to ensure they were apparently normal areas, without visible signs of cancer in imaging exams or pathological analyses.

When investigating these samples, the scientists discovered something surprising: in about forty percent of patients with IDH-mutated glioma, the initial mutation of the IDH gene was also present in non-tumorous brain regions that were relatively distant from the cancer site.

In these areas, the mutation was present at very low levels and there were no other mutations associated with cancer. This suggests that these mutated cells existed in the brain before tumor formation and remained apparently normal for a prolonged period.

More detailed analyses showed that these initial mutations were concentrated in a specific type of brain cell: glial progenitor cells. These cells are responsible for generating different types of supporting brain cells.

Within this group, a specific subtype stood out: oligodendrocyte progenitor cells, which normally help in the formation of myelin, the layer that isolates and protects neurons. Even with a normal appearance under a microscope, these cells already carried the genetic mutation that would later give rise to the tumor.

To confirm whether these cells could actually initiate glioma, the researchers created an experimental model in mice. In this model, specific mutations, including the mutation in the IDH gene and other mutations known to promote cancer, were introduced directly into human oligodendrocyte progenitor cells. Over time, these mutated cells began to multiply uncontrollably, accumulated new genetic alterations, and evolved into brain tumors.

The tumors formed in mice were extremely similar to human IDH-mutant gliomas, both in tissue structure and in how genes were activated and deactivated. This provided strong experimental evidence that glial progenitor cells, especially oligodendrocyte progenitor cells located in seemingly normal brain regions, may be the true origin of these tumors.

These results change how we understand the development of IDH-mutant gliomas. Instead of suddenly appearing as aggressive tumors, they seem to begin silently, from seemingly healthy cells that carry an initial mutation for years, until they acquire new genetic alterations that lead to cancer. This knowledge opens new possibilities for early diagnosis and potentially for interventions before the tumor becomes clinically detectable.

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IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation

Jung Won Park, Jiehoon Kwak, Keon-Woo Kim, Saehoon Jung, Chang Hyun Nam, Hyun Jung Kim, Sang Mee Lee, Chanho Choi, Yongjin Ahn, Ji-Hyung Park, Jihwan Yoo, Jin-Kyoung Shim, Hye Joung Cho, Eui-Hyun Kim, Chungyeul Kim, Sangjeong Ahn, Stefan Pusch, Andreas von Deimling, Jong Hee Chang, Se Hoon Kim, Hoon Kim, Young Seok Ju, Seok-Gu Kang, and Jeong Ho Lee

Science. VOL. 391, NO. 6781. 8 January 2026.

DOI: 10.1126/science.adt0559

Abstract:

Identifying the cell of origin that harbors an initial driver mutation is key to understanding tumor evolution and for the development of new treatments. For isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumor in young adults, the cell of origin is currently poorly understood. We conducted deep sequencing on 142 tissues from 70 individuals comprising tumors, peritumoral cortex or subventricular zones, and blood. Low-level IDH mutations were found in the peritumoral cortex in 37.9% (11 of 29) of patients. Integrating cell-type-specific mutation analysis, the direction of clonal evolution, spatial transcriptomics from patient brains, and a cancer mouse model arising from mutant oligodendrocyte progenitor cell, we determined that glial progenitor cells harboring an initial IDH mutation were responsible for the development of IDH-mutant gliomas.