Isocitrate dehydrogenase (IDH) mutations are genetic alterations impacting an enzyme, playing a significant role in various cancers. These mutations affect how cells metabolize and produce energy. Understanding these changes is important for cancer research and for developing new treatment strategies. Research continues to clarify how these mutations contribute to cancer development and how they can be targeted for therapy.
What is IDH and Its Normal Role?
Isocitrate dehydrogenase (IDH) is a family of enzymes found within the body’s cells, playing a part in cellular metabolism and energy production. There are three main forms of IDH in humans: IDH1, IDH2, and IDH3.
IDH1 is primarily located in the cytoplasm and in peroxisomes. IDH2 is found in the mitochondria. Both IDH1 and IDH2 are involved in a reversible reaction that converts isocitrate to alpha-ketoglutarate (α-KG), while also producing NADPH. NADPH is a molecule that helps protect cells from damage and is involved in building other molecules, such as fats.
IDH3, also in the mitochondria, is a separate enzyme that uses NAD+ to produce NADH as part of the Krebs cycle. This cycle is a central pathway for breaking down nutrients to generate energy for the cell. The normal function of IDH enzymes contributes to energy balance, cellular defense against oxidative stress, and the regulation of other enzyme activities.
How IDH Mutations Drive Cancer
A mutation in the IDH gene, specifically in IDH1 or IDH2, alters the enzyme’s normal function. These mutations most commonly occur at specific amino acid positions, such as R132 in IDH1 or R140 and R172 in IDH2. Instead of converting isocitrate to α-KG, the mutated IDH enzyme now converts α-KG into 2-hydroxyglutarate (2-HG).
This 2-HG is an “oncometabolite” because its accumulation contributes to cancer development. Elevated levels of 2-HG interfere with normal cellular processes, particularly those involving enzymes that depend on α-KG for their function. These α-KG-dependent enzymes are crucial for epigenetic regulation, which involves changes in gene expression without altering the underlying DNA sequence.
Specifically, 2-HG inhibits enzymes involved in epigenetic regulation. This inhibition leads to widespread epigenetic changes, including increased DNA methylation and histone methylation. DNA methylation involves adding chemical tags to DNA, which can silence genes, while histone modifications affect how DNA is packaged, influencing gene accessibility. These epigenetic alterations disrupt normal cell differentiation, preventing cells from maturing properly and causing them to remain in an immature, rapidly dividing state, contributing to uncontrolled cell growth and tumor formation.
IDH Mutations in Cancer Diagnosis and Treatment
Identifying IDH mutations has become important in the diagnosis and management of certain cancers. These mutations are frequently found in specific types of tumors, including gliomas (brain tumors), acute myeloid leukemia (AML), and cholangiocarcinoma (bile duct cancer). For example, IDH1 mutations are common in lower-grade gliomas, while both IDH1 and IDH2 mutations are found in a subset of AML patients.
The presence of an IDH mutation can influence a cancer’s behavior and often indicates a distinct biological subtype with a generally better prognosis compared to tumors without these mutations. For instance, in gliomas, IDH-mutant tumors may respond more favorably to certain therapies. Testing for IDH mutations is a standard part of tumor biomarker analysis, helping clinicians categorize tumors, predict disease progression, and make informed treatment decisions.
The understanding of IDH mutations has led to the development of targeted therapies known as IDH inhibitors. These drugs are designed to specifically block the abnormal activity of the mutated IDH enzyme, reducing the production of the oncometabolite 2-HG. By lowering 2-HG levels, IDH inhibitors can help restore normal cellular differentiation and potentially slow or halt tumor growth. Several IDH inhibitors are currently approved or under investigation for patients with IDH-mutant cancers.