SNP Shot: Genomic Insights

A gastrointestinal stromal tumor (GIST) is a tumor that develops in the digestive tract, most often in the stomach or small intestine. It's believed these tumors originate from specialized cells in the GI tract called interstitial cells of Cajal (ICCs) or their precursors. Individuals may develop a single tumor or multiple tumors. GISTs are most frequently diagnosed in adults between 40 and 70 years old, though they can rarely occur in children and young adults.

Small GISTs might not cause any noticeable symptoms. However, some individuals with GISTs may experience abdominal pain or swelling, nausea, vomiting, loss of appetite, or weight loss. Sometimes, these tumors can bleed into the digestive tract, leading to anemia (low red blood cell count), resulting in weakness and fatigue. This bleeding can manifest as black, tarry stools if it occurs in the intestines, or as vomiting blood if it occurs in the throat or stomach.

Individuals with GIST who have no family history of the condition typically develop only one tumor, which is called a sporadic GIST. In contrast, people with a family history of GISTs (familial GISTs) often have multiple tumors and may exhibit other signs and symptoms, such as noncancerous overgrowth (hyperplasia) of other cells in the GI tract and dark skin patches on different parts of their body. Some individuals might also have urticaria pigmentosa, a skin condition characterized by raised, brownish skin patches that sting or itch when touched (also known as maculopapular cutaneous mastocytosis).

A rare type of GIST, called succinate dehydrogenase (SDH)-deficient GIST, is more common in childhood or young adulthood and affects females more often than males. In this form, tumors almost always appear in the stomach. Individuals with SDH-deficient GIST have an increased risk of developing other types of tumors, especially noncancerous tumors in the nervous system called paragangliomas and noncancerous lung tumors called pulmonary chondromas. The combination of GISTs and paragangliomas is known as Carney-Stratakis syndrome. The combination of GISTs, paragangliomas, and pulmonary chondromas is known as Carney triad, and the combination of GISTs and pulmonary chondroma is known as incomplete Carney triad.

Inheritance:

Most GIST cases are sporadic, meaning they are not inherited. These cases are caused by a somatic mutation, a genetic change that happens only in the tumor cells during a person's lifetime.

Some cases of familial GIST, including those linked to mutations in the KIT and PDGFRA genes, typically follow an autosomal dominant inheritance pattern. This means that inheriting only one copy of the altered gene in each cell is enough to increase the risk of developing tumors. However, a second somatic mutation is necessary for a tumor to form.

When familial GIST is caused by mutations in other genes, it can follow an autosomal recessive inheritance pattern. This means that alterations in both copies of the gene in each cell are needed to increase the likelihood of developing tumors.

SDH-deficient GIST is inherited in an autosomal dominant pattern; a mutation in one copy of the SDHA, SDHB, SDHC, or SDHD gene is enough to increase the risk of developing tumors. A second somatic mutation altering the other copy of the gene is needed for tumor formation. A particular alteration in the SDHC gene is not inherited and is usually associated with Carney triad.