Isocitrate Dehydrogenase (IDH)-Mutant Astrocytoma

The IDH gene encodes an enzyme by the same name that is part of the citric acid cycle – a series of interconnected biochemical reactions that process sugars, fats, and proteins into energy for the cell. It has two different forms (IDH1 and IDH2) that serve this identical function in the cytoplasm and the mitochondria of cells, respectively. When the IDH gene is mutated, rather than convert the metabolite isocitrate into alpha-ketoglutarate, cells instead produce a harmful byproduct that promotes tumor growth called 2-hydroxyglutarate (2-HG).¹ 

IDH mutations can be readily identified through histology with an antibody that binds to the mutated versions of the enzyme or through genomic sequencing.

Some common symptoms may include the following:

• Headaches
• Seizures

While seizures are often symptoms of other types of brain tumors, including glioblastoma, they tend to occur more frequently in patients with IDH-mutant gliomas.

Additional symptoms depend on the size and location of the tumor, which may impact specific neurological functions. For example, an IDH-mutant astrocytoma near the motor cortex (which controls body movement) may cause slowly progressive weakness on one side of the body.

IDH-mutant astrocytomas are the second most common glioma, after glioblastoma, accounting for approximately 10-11% of all primary brain tumors.² However, because these tumors have a more favorable prognosis than glioblastoma, they account for most people living with glioma.^2,3 Most cases occur in adults, although they occasionally develop in children as well.

As their name suggests, IDH-mutant astrocytomas are characterized by mutations in the IDH1 or IDH2 genes. IDH-mutant astrocytomas must also carry mutations in the ATRX and TP53 genes.⁴ The ATRX gene encodes a protein that regulates transcription (the process by which RNA is made from DNA), and the TP53 gene encodes the p53 tumor suppressor protein, which plays an important role in controlling cell growth and protecting cells from DNA damage.

Historically, diffuse astrocytomas and anaplastic astrocytomas were considered distinct entities, but the latest World Health Organization classification scheme for diffuse gliomas now groups all IDH-mutant astrocytomas as single type of tumor.⁴ This is because the IDH mutation status predicts patient outcomes better than relying solely on what the tumor cells look like under the microscope (its histological features).⁵

IDH-mutant astrocytomas are “graded” based on how abnormal the tumor cells look under the microscope in addition to several other molecular alternations. Grade 3 IDH-mutant astrocytomas have more genetic alternations and “anaplastic” features, which include cell nuclei that are an irregular shape or size and more actively dividing cells.⁶ IDH-mutant astrocytomas that have homozygous deletion of CDKN2A/B and/or have signs of lots of irregular blood vessels (microvascular proliferation) and necrosis (areas of dead tissue) are classified as grade 4.⁴ 

Depending on the size and location of the tumor, patients with IDH-mutant astrocytoma are usually first treated with surgery. The primary objective is to remove as much of the tumor as possible while protecting critical brain function. This is called maximal safe resection. Especially since these tumors can occur in near areas of the brain that control body movement, language, or vision, special measures may be taken to protect these functions. For example, awake surgery with brain mapping is commonly used when tumors are located in the brain regions that control language or movement. This technique allows surgeons to safely identify and preserve critical brain regions.

Chemotherapy and radiation may be suggested in addition to surgery, depending on the tumor’s size, location, and extent of surgical removal. 

The IDH inhibitor vorasidenib may also be a treatment option for patients with grade 2 IDH-mutant astrocytomas, especially those with residual disease after surgery. This targeted drug therapy, taken once daily as an oral pill, may help slow tumor growth.

Neurocognitive rehabilitation is also available through our Neurocognitive Care Services. Our multi-disciplinary team will assess each patient's needs, and devise an individualized plan to improve language, motor, or cognitive impairments caused by the brain tumor.

How well a patient with IDH-mutant astrocytoma responds to treatment depends on a variety of factors, including the tumor grade, extent of surgical resection, age, and general health characteristics.

Typically, complete surgical removal of the tumor visible on the MRI offers the best patient outcomes for long-term survival. However, IDH-mutant astrocytoma can recur after surgery, so patients are regularly monitored for both tumor recurrence and progression to a higher-grade tumor.

Grade 2 IDH-mutant gliomas are slow-growing tumors and hold a better prognosis than grade 3-4 IDH-mutant gliomas, which are high-grade gliomas, and progress more rapidly.

Finding information about prognoses and survival rates is a personal decision. The current statistics are only summary data, and don’t necessarily reflect results from new or experimental therapies. These data do not determine how individual patients might respond to their treatment – everyone is different. That said, some people may choose to look for this information, which can be found in the most recent CBTRUS Statistical Report, in Tables 15-18.²

1. Rudà, R., Horbinski, C., van den Bent, M., Preusser, M., & Soffietti, R. (2024). IDH inhibition in gliomas: from preclinical models to clinical trials. Nature reviews. Neurology, 20(7), 395–407. https://doi.org/10.1038/s41582-024-00967-7
2. Price, M., et al. (2024). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2017-2021. Neuro-oncology, 26(Supplement_6), vi1–vi85.
3. Molinaro, A. M., Taylor, J. W., Wiencke, J. K., & Wrensch, M. R. (2019). Genetic and molecular epidemiology of adult diffuse glioma. Nature reviews. Neurology, 15(7), 405–417.
4. Louis, D. N., et al (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncology, 23(8), 1231–1251.
5. Cancer Genome Atlas Research Network, et al. (2015). Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. The New England journal of medicine, 372(26), 2481–2498. https://doi.org/10.1056/NEJMoa1402121
6. Kros, J. M., et al. (2023). Mitotic count is prognostic in IDH mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trial 26053 (CATNON) and EORTC trial 22033-26033. Neuro-oncology, 25(8), 1443–1449.