Gastrointestinal Stromal Tumor (GIST) Causes

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Cancers are born when the DNA of a cell changes in some specific ways. The DNA or genetic material of a cell is what contains the genes, the code which controls all of the body’s functions and anatomy. The DNA of every individual is passed down from both parents.

The genes that promote cell growth and proliferation at an excessive rate, free of normal regulatory controls, are called oncogenes. There are also tumor suppressor genes which delay cell division or induce apoptosis of damaged or senescent cells. Any change in the DNA which activates one or more oncogenes, or switches off tumor suppressor genes, is called a carcinogenic mutation.

What is a GIST Tumor

Some Genetic Mutations Linked to GIST Development

Many mutations have now been uncovered in connection to GISTs, but the reason for these changes remains unclear. Some of them are possibly related to the lifestyle or environment, but others may be spontaneous mutations. These have no obvious cause and are called sporadic or acquired mutations.

KIT or PDGFRA Mutations

Most GIST cells (about 80%) show a mutation in the KIT gene, an oncogene which regulates the production of the KIT protein. This protein is a growth promoter and encourages cell proliferation. GISTs originate in certain cells called the interstitial cells of Cajal, or ICCs, within which the KIT protein is generally inactive. However, in a patient with GIST, the mutated KIT gene is activated and this leads to unregulated cellular growth and division. The KIT gene expresses a receptor protein on the cell membrane of certain cells, which can be bound by a specific ligand to activate one or more intracellular signal pathways, involving multiple proteins. These pathways are feedback-dependent and thus subject to the regulation of the processes they mediate, such as cell growth, proliferation, and survival. Once a mutation occurs in this gene, the resulting protein that is expressed becomes autonomous. Another term for this is that the expression of these proteins and the signaling pathway itself becomes a constitutive feature or one that is turned on without any need for cellular switch-on signals. This enhances cell survival and proliferation in an unregulated manner, leading, in this case, to a GIST.

The KIT gene encodes a tyrosine kinase which triggers the runaway growth of the GIST cells.

While the KIT mutation is the most common, the PDGFRA gene is affected in 5-10% of patients. This is responsible for the expression of PDGFRA, another cell growth promoter protein.

The majority of GIST tumors show either KIT or PDGFRA gene mutations, with both rarely seen in the same tumor.

Familial GIST

Some families have a mutation that is transmitted through generations and which causes GIST. This may affect either the KIT or the PDGFRA genes, and rarely other genes.

Other Mutations

A very few GISTs have no KIT or PDGFRA mutations, especially in children. In these tumors mutations in one of the SDH genes are observed in many cases, but other mutations remain to be identified. These tumors are called wild-type GISTs or pediatric-like GISTs. They account for about 10-15% of adult GISTs and 85% of pediatric GISTs.

Risk Factors for GIST

The most significant risk factor for GIST is neurofibromatosis, itself a proliferative genetic condition. A family history of GIST is another risk factor, though much less commonly associated with GIST.

Further Reading

Last Updated: Feb 20, 2023

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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