SDH-Deficient GIST Glossary

DNA hypermethylation – DNA methylation is a process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. Alterations of DNA methylation have been recognized as an important component of cancer development. Hypermethylation is associated with gene promoters and can arise secondary to gene (oncogene suppressor) silencing but might be a target for epigenetic therapy.

Fumarate – A salt or ester of fumaric acid. (Fumaric acid is produced in eukaryotic organisms from succinate in complex 2 of the electron transport chain via the enzyme succinate dehydrogenase. The salts and esters are known as fumarates. – Wikipedia.)

Hypoxia-inducible factor (HIF) – Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. There is a critical role for HIF-1 in the regulation of genes involved in a variety of important biological processes that include glucose transport and metabolism, vascular growth, vasomotor regulation, erythropoiesis, iron metabolism, and catecholamine synthesis.

Immunohistochemistry (IH, IHC, or IHC Stain) – A lab test that uses antibodies to test for certain antigens (markers) in a sample of tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. When the antibodies bind to the antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. Immunohistochemistry is used to help diagnose diseases, such as cancer. It may also be used to help tell the difference between different types of cancer. In GIST, an IHC stain is used to confirm an initial GIST diagnosis, and a separate IHC stain to test whether a patient has the SDH-deficient version of the disease.

Krebs Cycle – The sequence of reactions by which most living cells generate energy during the process of aerobic or oxygen-based respiration. SDH is a key component of this cycle, and when it is deficient the cycle is affected.

Promoter Hypermethylation – Promoter hypermethylation is an important pathway for the repression of gene transcription in cancer.

Succinate – A salt or ester of succinic acid.

Succinate dehydrogenase (SDH) – SDH is an enzyme. Enzymes typically act as catalyzers or substances that initiate or increase the rate of a chemical reaction, often dramatically. SDH speeds up the conversion of succinate to fumarate. This conversion is a key part of cell metabolism. SDH has four components (A, B, C & D).  All four combine to form the SDH complex. If one component is faulty the complex cannot work.  SDH is a key component of the cell energy cycle called the Krebs cycle that drives every cell.

 SDH Deficient GIST – GIST tumor tissue that stains negative for SDHB IHC.

Mutant SDH-deficient GIST – Tumor tissue that is SDHB IHC negative and SDH gene mutation tests positive for SDH A, B, C or D mutation.

• Somatic Mutant SDH-deficient GIST – Tumor tissue that is SDHB IHC negative. SDH gene mutation test is positive for SDH A, B, C or D mutation. Normal tissue (cheek swab) SDH mutation test shows no mutations in SDH A, B, or C.
• Germline Mutant SDH-deficient GIST –  Tumor and normal tissue (cheek swab) test positive for the same SDH A, B, C or D mutation.

Epimutant SDH-deficient GIST –  Tumor tissue is SDHB IHC negative and mutation test shows no SDH A, B, C or D mutations. Confirmable by separate testing for SDHC hypermethylation. This is important to distinguish from other forms of SDH-deficient GIST as due to its hypermethylated nature it may respond to different treatments.