Gastrointestinal Stromal Tumor (GIST) Causes and Risk Factors

Gastrointestinal stromal tumors develop when specialized cells within the walls of the digestive tract acquire genetic changes that cause them to grow uncontrollably and form tumors. The exact cause of most GISTs is unknown, but many are driven by mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes, which normally help regulate cell growth, division and survival. GISTs are diagnosed primarily in older adults, and a small percentage are associated with inherited genetic syndromes.

Although rare, gastrointestinal stromal tumors are the most common connective tissue (mesenchymal) tumors of the gastrointestinal tract. According to the National Cancer Institute, approximately 4,000 to 6,000 people are diagnosed with a GIST in the United States each year. 

What causes gastrointestinal stromal tumors? 

GISTs arise from specialized cells called interstitial cells of Cajal (ICCs), which help coordinate the muscular contractions that move food through the digestive tract. When these cells develop certain genetic abnormalities, they may begin to grow uncontrollably and eventually form a tumor.

While researchers do not fully understand why most GISTs develop, they have identified several molecular changes that disrupt the normal regulation of cell growth within ICCs, allowing abnormal cells to continue dividing instead of responding to the body's normal growth-regulating controls.

Potential biological mechanisms involved in gastrointestinal stromal tumor development include:

• KIT gene mutations – Most GISTs result from acquired mutations in the KIT gene. These changes cause the KIT protein to remain continuously active, promoting uncontrolled cell growth.
• PDGFRA gene mutations – Some GISTs are driven by alterations in the PDGFRA gene, which can also promote abnormal cell growth.
• Changes in cell-signaling pathways – Alterations affecting proteins that regulate cell growth, survival and communication may contribute to GIST development.
• Inherited genetic syndromes – Although uncommon, some GISTs develop as part of hereditary conditions, such as neurofibromatosis type 1 (NF1) and familial GIST syndrome, which increase susceptibility to these tumors.

What are the risk factors for gastrointestinal stromal tumors?  

Most GISTs occur sporadically without a clearly identifiable cause. However, researchers have identified several characteristics and inherited conditions that may increase the likelihood of developing gastrointestinal stromal tumors. These include:

• Increasing age – GISTs are diagnosed most often in adults older than 50.
• Inherited KIT or PDGFRA gene mutations – Rare inherited mutations in these genes can increase the likelihood of developing multiple GISTs.
• Neurofibromatosis type 1 (NF1) – Individuals with NF1 have an increased likelihood of developing certain gastrointestinal stromal tumors, particularly in the small intestine.
• Carney-Stratakis syndrome – This uncommon inherited condition is associated with GISTs and paragangliomas.
• Carney triad – This rare syndrome is associated with an increased likelihood of developing GISTs, particularly in younger women. Unlike Carney-Stratakis syndrome, Carney triad is generally not inherited and may also involve pulmonary chondromas and paragangliomas.
• Familial GIST syndrome – Although rare, families with inherited KIT or PDGFRA mutations may develop multiple gastrointestinal stromal tumors.

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Which risk factors for gastrointestinal stromal tumors are nonmodifiable?

Several recognized risk factors for GISTs cannot be changed. Understanding these characteristics may help identify individuals who could benefit from genetic counseling or specialized surveillance. Nonmodifiable risk factors for gastrointestinal stromal tumors include:

• Increasing age – GISTs are diagnosed most often in adults older than 50.
• Inherited KIT or PDGFRA mutations – Although most KIT and PDGFRA mutations occur after birth, rare inherited mutations can significantly increase the risk.
• Inherited syndromes – Certain conditions, including familial GIST syndrome, Carney-Stratakis syndrome and neurofibromatosis type 1, increase susceptibility to gastrointestinal stromal tumors.
• Carney triad – Although not inherited, this rare condition is associated with an increased likelihood of developing GISTs, particularly in younger women.
• Family history of GISTs – Individuals with one or more close relatives affected by hereditary GIST syndromes may have an increased likelihood of developing gastrointestinal stromal tumors.

Which risk factors for gastrointestinal stromal tumors are modifiable?

No well-established modifiable risk factors have been identified. However, certain healthcare measures may be appropriate for individuals with persistent symptoms or inherited GIST syndromes. These include:

• Prompt evaluation of concerning symptoms – Persistent abdominal pain, blood in the stool, black or tarry stools, difficulty swallowing, unexplained fatigue and other unusual symptoms should be evaluated by a healthcare provider.
• Specialized surveillance for hereditary GIST syndromes – Individuals with inherited conditions associated with gastrointestinal stromal tumors should follow the individualized monitoring plans and regular medical follow-up recommended by their healthcare team.

Can gastrointestinal stromal tumors be prevented?

Because most GISTs have no identifiable cause and are not associated with preventable lifestyle factors, there is no established way to prevent them. However, the following measures may help identify inherited risk, support earlier diagnosis and facilitate timely treatment:

• Sharing family medical history – Individuals who have one or more close relatives with a hereditary GIST syndrome should discuss their family history with a healthcare provider.
• Considering genetic counseling – Genetic counseling and testing may be appropriate for individuals with a personal or family history suggestive of an inherited GIST syndrome.
• Seeking prompt evaluation for persistent digestive symptoms – Abdominal discomfort, blood in the stool, black or tarry stools, early fullness (satiety) or unexplained anemia should be evaluated promptly by a physician.
• Following recommended surveillance plans – Individuals with an inherited genetic syndrome associated with GISTs may benefit from periodic imaging, endoscopic evaluations or other monitoring recommended by their healthcare team.
• Maintaining routine medical care – Regular healthcare visits can help identify concerning symptoms that warrant additional evaluation.

Find the help you need for gastrointestinal stromal tumors at Moffitt Cancer Center 

Learning that a GIST may be associated with specific genetic changes or an inherited syndrome can raise important questions about diagnosis, treatment and family risk. The multispecialty team in Moffitt's Gastrointestinal Oncology Program provides comprehensive evaluations, expert pathology reviews, advanced molecular testing and individualized treatment plans for patients with GISTs and other rare gastrointestinal tumors.

If you would like to learn more about gastrointestinal stromal tumor causes, risk factors or treatment options, you can request an appointment with a specialist at Moffitt by calling 1-888-663-3488 or submitting a new patient registration form online. We do not require referrals.