IDH1 and IDH2 are genes that provide instructions for making proteins called isocitrate dehydrogenase 1 and 2. These proteins help cells produce energy by participating in a normal chemical process that converts one molecule (isocitrate) into another (α-ketoglutarate), a process essential for many cellular functions. These proteins also help regulate the balance of other molecules that support healthy cell growth and repair.
Mutations (changes) in the IDH1 and IDH2 genes can disrupt this process, leading to the formation of abnormal molecules that cause cells to grow and behave in unusual ways. These mutations are found in several types of tumours and are especially important in diagnosing and classifying brain tumours, such as diffuse gliomas.
The normal versions of the IDH1 and IDH2 genes are found in nearly all human cells and play a role in energy production. However, the IDH1 R132H mutation, the most common mutation in brain tumors, is not found in normal tissue. That’s why this mutation can be a strong signal that a tumour is present when detected in a tissue sample.
Pathologists test for mutations in IDH1 and IDH2 using two main methods:
Immunohistochemistry (IHC): This test uses a special antibody that detects the most common IDH1 mutation (called IDH1 R132H). If the mutation is present, the tumour cells will show a visible stain in the cytoplasm of the cells under the microscope. A positive result means the mutation is present. A negative result means the mutation is either not present or it may be a less common type not detected by this test.
Molecular testing: If IHC is negative or more detailed information is required, pathologists can utilize genetic testing methods, such as next-generation sequencing (NGS), to investigate for additional IDH1 or IDH2 mutations. These tests can detect a broader range of mutations not seen by IHC.
IDH1 and IDH2 mutations have been found in the following types of tumours.
Acute myeloid leukemia (AML) – IDH1 and IDH2 mutations are found in about 20% of AML cases. These mutations often occur in conjunction with other genetic changes and are more prevalent in older adults and those with intermediate-risk cytogenetics. IDH1 mutations are associated with slightly worse outcomes, while specific IDH2 mutations may be linked to a better prognosis.
Chondrosarcoma – About 40–50% of these bone cancers carry IDH1 or IDH2 mutations, and these are associated with a worse overall survival.
Cholangiocarcinoma (intrahepatic bile duct cancer) – A cancer of the bile ducts in the liver. Approximately 25% of these tumours carry an IDH mutation.
Sinonasal undifferentiated carcinoma – A rare aggressive type of nasal cavity cancer where a high proportion (49–80%) have IDH2 R172 mutations.
Spindle cell hemangioma and Ollier disease/Maffucci syndrome – These benign tumors are associated with mosaic IDH1 or IDH2 mutations.
Osteosarcoma – An aggressive type of bone cancer where around 25% of cases harbor an IDH2 mutation, typically the R172S type.
IDH1 and IDH2 are important because the presence or absence of these mutations can help doctors better understand the type of tumor, its potential behavior over time, and which treatments may be most effective.
Help diagnose and classify tumors more accurately. In the brain, IDH mutations are a key feature of certain types of gliomas, helping to distinguish them from other brain tumors. In the bone, cartilage, and soft tissues, IDH mutations may support a diagnosis of specific tumors, such as chondrosarcoma or spindle cell hemangioma.
Provide important prognostic information. For example, IDH-mutant gliomas tend to grow more slowly and respond better to treatment than gliomas without these mutations. In contrast, IDH1 mutations in acute myeloid leukemia (AML) are often associated with lower remission rates and shorter survival. The significance of the mutation can vary depending on the type of cancer.
Guide the use of targeted therapies. New treatments are now available that specifically target IDH1 or IDH2 mutations in some cancers, such as AML. These drugs, known as IDH inhibitors, can slow tumor growth and help cancer cells mature into more normal cells. Similar drugs are being investigated for use in other types of cancer.
Support the diagnosis of rare inherited conditions. In some cases, identifying an IDH mutation can also indicate an underlying inherited condition, such as Ollier disease or Maffucci syndrome. These conditions are linked to IDH mutations and cause multiple benign cartilage or blood vessel tumors to develop, often early in life.
Understanding whether a tumor has an IDH mutation is an important part of many pathology reports and can help guide both diagnosis and treatment.
Does my tumour have an IDH1 or IDH2 mutation?
What does this mutation mean for my diagnosis and prognosis?
Are there treatments available that specifically target this mutation?
Should I have additional molecular testing for other gene mutations?
How might this information affect my treatment plan?