Isocitrate dehydrogenase (IDH) enzymes play a fundamental role in normal cellular metabolism. These enzymes are involved in the tricarboxylic acid (TCA) cycle, which helps cells produce energy. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), a molecule involved in various cellular processes. The term “wild type” in a biological context refers to the naturally occurring form of a gene or enzyme, meaning it does not carry any mutations. While this typically indicates normal, healthy function, the status of IDH as “wild type” or “mutated” holds significant implications in the context of certain diseases, particularly cancers.
IDH Wild Type Versus Mutated IDH
The distinction between IDH wild type and mutated IDH lies in a specific genetic alteration that profoundly changes the enzyme’s function. In the case of IDH, mutations frequently occur at specific “hotspot” locations on the IDH1 or IDH2 genes, such as IDH1 R132 or IDH2 R140 and R172. These mutations do not simply inactivate the enzyme; instead, they confer a new, abnormal function, known as neomorphic activity. The mutated IDH enzyme gains the ability to convert α-KG into an abnormal metabolite called 2-hydroxyglutarate (2-HG). This accumulation of 2-HG, often at levels 10 to 100 times higher than normal, is considered an “oncometabolite” because it interferes with normal cellular processes. This disruption of normal cell regulation contributes to the development and progression of cancer. Therefore, the presence or absence of this specific mutation—determining whether the IDH enzyme is “wild type” or “mutated”—is medically significant, influencing disease behavior and potential treatment strategies.
Role in Specific Cancers
The status of IDH, whether wild type or mutated, significantly impacts the biological behavior and clinical characteristics of certain cancers. IDH wild type gliomas, especially glioblastoma (GBM), are more aggressive and carry a poorer prognosis compared to IDH-mutated gliomas. Glioblastoma, IDH wild type, is the most common and aggressive primary brain tumor in adults. These tumors frequently exhibit chromosomal abnormalities, such as loss of material in chromosome 10q and gain in chromosome 7p, and mutations in the TERT promoter gene. The median survival for patients with IDH wild type glioblastoma is often less than 15 months, although factors like age under 20 years and complete surgical resection can improve outcomes. In contrast, IDH mutations in gliomas are associated with a longer overall survival. For acute myeloid leukemia, IDH mutations are found in approximately 20% of cases, with IDH2 mutations being slightly more common than IDH1 mutations. While initial studies on the prognostic significance of IDH mutations in AML have shown mixed results, some research suggests that overall survival for both IDH-mutated and IDH wild-type AML patients can be comparable, particularly in certain treatment settings. However, other studies indicate that AML patients with IDH1 mutations may have inferior overall survival compared to those without the mutations.
Diagnostic and Prognostic Significance
Determining IDH status is important for accurate cancer diagnosis and classification. This status is assessed through molecular testing of tumor tissue. Methods include immunohistochemistry (IHC), which uses special dyes to detect the presence of the mutated IDH protein in tissue samples. Genetic testing, such as DNA sequencing, directly analyzes the DNA of the tumor cells to identify specific mutations in the IDH1 or IDH2 genes. For instance, targeted massively parallel sequencing (also known as next-generation sequencing) can identify hotspot variants in IDH1 and IDH2. This testing provides prognostic information, influencing the predicted course and outcome of the disease. In gliomas, IDH wild type status generally indicates a more aggressive disease and a less favorable prognosis compared to IDH-mutated counterparts. Similarly, in AML, while the prognostic impact of IDH mutations can be complex and sometimes comparable to wild type, certain genetic changes associated with IDH wild type status can still influence the predicted outcome.
Therapeutic Implications
The IDH wild type status guides treatment decisions. For IDH-mutated cancers, specific inhibitors like ivosidenib (for IDH1-mutated AML) and vorasidenib (for IDH-mutant gliomas) are approved or under investigation. These targeted therapies are designed to block the abnormal 2-HG production by the mutant enzyme. However, for IDH wild type cancers, standard treatment approaches are employed. In IDH wild type glioblastoma, treatment involves maximal safe surgical removal of the tumor, followed by a combination of radiation therapy and chemotherapy, often using temozolomide. This multimodal approach aims to slow tumor growth and improve patient outcomes. For older patients or those with poorer health, modified radiation regimens, sometimes with temozolomide, may be considered. Research continues to explore new avenues for IDH wild type cancers. For example, some studies suggest that targeting wild type IDH1 in glioblastoma cells, which can be involved in therapeutic resistance, could have potential. Ongoing clinical trials are evaluating various strategies, including new radiation therapy doses and volumes, and combinations of chemotherapy drugs like temozolomide and lomustine for IDH wild type gliomas.