Does every person with a germ-line c-kit or PDGFRA mutation develop GIST?
No, not everyone with a germ-line c-kit or PDGFRA mutation will develop GIST. A study of one large family with a germ-line c-kit mutation estimated that individuals who carried this alteration might have up to a 90% risk of developing GIST by age 70. However, more data are needed to determine whether this estimate applies to all possible mutations within the c-kit and PDGFRA genes, and to find out whether anything can increase or reduce these risks.
It is also unclear why the symptoms, location, age at diagnosis, and clinical course of some GISTs differ from other GISTs, even within the same family where individuals carry the same germ-line mutation. It is likely that other unknown genetic, environmental, or lifestyle factors also contribute to the development of GIST, even in people with an inherited susceptibility.
What are the clinical steps for identifying familial GIST?
The first step in identifying familial GIST is to speak with a physician, a genetic counselor, or another genetics professional to review your personal and family history. Based on the information you provide, they can help evaluate the risk that your family has a familial form of GIST and determine whether additional genetic evaluation is warranted.
If appropriate, based on your personal and family history, an affected family member (someone who has had GIST) may be advised to undergo genetic testing to determine whether the family carries a germ-line mutation in the c-kit or PDGFRA gene. Genetic tests are performed on a sample of DNA from blood or saliva. If a mutation is identified in one of these genes, other family members can then undergo genetic testing to determine whether they have also inherited the familial mutation. Only relatives who carry the familial mutation are at increased risk of developing GIST; those who do not inherit the mutation do not share this increased risk.
There are many factors to consider before deciding whether to proceed with genetic testing, and these can be discussed with a physician or another genetics professional. To locate a genetic counselor in your area, visit the website for the National Society of Genetic Counselors and use the “Find a Counselor” tool. Because so little is known about inherited GIST, however, many genetic counselors may not be very familiar with it at first.
When would an individual become suspicious that his/her family may have familial GIST?
Any of the following features may suggest that familial GIST is present:
(a) One person in the family was diagnosed with GIST at an unusually early age (generally before age 50) OR
(b) One person in the family who has developed more than one separate primary (new GIST, not a metastasis) GIST tumor OR
(c) Two or more close relatives with GIST OR
(d) One person in the family with GIST who also has a close relative with another rare type of tumor OR
(e) One person in the family with GIST who also has a personal or family history of unusual skin findings, multiple moles or NF1
Not all families with these features will have familial GIST. Likewise, some families who turn out to have familial GIST may not show these features at all. However, these combinations of GIST and other findings are rare enough that they suggest additional genetic evaluation may be warranted.
Can some people have milder effects instead of GIST tumors?
Beside GISTs, other, milder features have also been reported in some families with germ-line mutations in the c-kit gene. These have primarily included:
(a) Skin findings, including pigmented or colored spots, areas of loss of coloration (“vitiligo”), multiple moles (“nevi”) and even melanoma (a skin cancer of the pigment cells), discoloration around the fingernails, and a group of conditions known as “mastocytosis” or “mast cell disease”
(b) Swallowing disorders that are not related to the GISTs themselves (also called “dysphasia” (difficulty swallowing) or “achalasia” (a specific disorder in which the esophagus doesn’t help to propel food to the stomach effectively)
Multiple families have also been reported with GIST alongside an inherited condition known as “neurofibromatosis type 1” (abbreviated NF1). NF1 is characterized by multiple café-au-lait spots and neurofibromas (benign growths) on the skin, as well as a distinctive pattern of freckling along the armpit and groin. Only a small subset of individuals with NF1 develop GISTs; other tumors may also occur with NF1. Germ-line mutations in the c-kit and PDGFRA genes have not been identified in patients with NF1 and GIST to date.
In a rare condition called Carney’s Dyad, individuals are at risk of developing GIST along with an even less common tumor called a paraganglioma. Along with another rare tumor called a pulmonary chondroma, this grouping of cancers was initially referred to as Carney’s Triad. The triad primarily occurred in young women and was not thought to run in families. More recent data has suggested that Carney’s Dyad may actually be distinct from Carney’s Triad. In addition, Carney’s Dyad is thought to be familial, occurring equally in men and women. At this time, mutations in c-kit, PDGFRA, and other genes have not been detected in families with either Carney’s Dyad or Triad. More work is needed to determine whether Carney’s Dyad and Triad are distinct genetic syndromes, or whether they arise through separate pathways.
View this video on Familial GIST