Familial GIST Frequently Asked Questions
1. Are inherited forms of GIST rare?
Are they found in any special populations around the world? Yes, heritable GIST is very rare – even rarer than most GISTs, which are called “sporadic” (not inherited). Only a small subset of people who develop GIST will do so because of a strong inherited tendency or “predisposition”. Approximately 15 families have been reported with familial GIST in the literature to date. These families have been from different countries and have a range of ethnic origins, so it appears that familial GIST does occur worldwide.
2. What is a germ-line mutation and how does it cause familial GIST?
A mutation is a change in the pattern of a gene’s DNA that prevents the gene from working properly. If you think of a gene as similar to a book, DNA is like the letters that make up the words in that book. Just as you can have a misspelling in a word in a book, you can have a misspelling (or “mutation”) in the DNA of one of your genes. Unlike a somatic mutation (which is present only in tumor cells), a germ-line mutation is present in every cell of your body from the time of your conception, so can be passed on or shared among family members.
There have been two genes identified to date that are involved in familial GIST. They are called c-kit and PDGFRA (platelet derived growth factor receptor alpha) gene. Mutations in the c-kit gene appear to be more common. If a person has a germ-line mutation in either of these genes, the gene can no longer function properly, which makes it easier for GISTs to develop. There may also be other cancer susceptibility genes that have not been discovered yet that are associated with GISTs in other families.
Each family (or “kindred”) with familial GIST may have its own unique germ-line mutation in a different part of a cancer susceptibility gene. Although the location of the germ-line mutation may be different from one family to another, the mutation will remain constant within a family: that is, the location of the mutation within the gene is the same for each member of a family.
3. Does every member of a familial GIST kindred have the mutation?
No, not every member of a kindred with familial GIST will inherit the familial mutation. We all typically have two copies of every gene: we inherit one copy of a gene from our mother and the other copy of a gene from our father. Similarly, if we have children, we pass on one of our two copies of a gene to each child and our partner contributes one of his/her two copies of a gene to make a complete set in a child. A person with a germ-line mutation in one of his or her c-kit or PDGFRA genes has a 50% (or 1 in 2) chance of passing on the same germ-line mutation to each of his or her children, with an equal 50% chance of passing on his or her unaltered copy of the gene. Mutations in the c-kit and PDGFRA genes can be inherited from your mother or from your father, and they are passed on to daughters and to sons equally. This is called an autosomal dominant pattern of inheritance.
Relatives who inherited the familial c-kit or PDGFRA germ-line mutation would be at increased risk to develop GIST. In addition, each of their children (or future children) would have a 1 in 2 chance of inheriting the familial germ-line mutation from them. Relatives who did not inherit the familial c-kit or PDGFRA germ-line mutation would not be at increased risk to develop GIST as compared to the general population, despite their family history. In addition, because they do not carry the familial mutation, they cannot pass it on to any of their children.
4. 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 in the family 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 is true of 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 not clear why the symptoms, location, age at diagnosis and clinical course of some GISTs are different from other GISTs, even within the same family in which individuals carry the same germ-line mutation. It is likely that other unknown genetic, environmental and/or lifestyle factors also contribute to the development of GIST, even in the presence of an inherited susceptibility.
5. 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)
There have also been multiple families reported with GIST and an inherited condition known as “neurofibromatosis type 1” (abbreviated NF1). NF1 is characterized by the development of 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 occur in NF1 as well. 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 the Carney's Dyad, individuals are at risk to develop GIST and 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 the Carney's Triad. The triad primarily occurred in young women, and was not thought to run in families. More recent data has suggested that the Carney's Dyad may actually be distinct from the Carney's Triad. In addition, the 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 the Carney's Dyad or Triad. More work is needed to determine whether the Carney's Dyad and Triad are distinct genetic syndromes or whether they arise through separate pathways.
6. 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. Similarly, other families who may turn out to have familial GIST may not exhibit these features. However, these combinations of GIST and other findings are rare enough to suggest that additional genetic evaluation may be warranted.
7. What are the clinical steps for identifying familial GIST?
The first step in identifying familial GIST would be to speak with a physician, genetic counselor or other genetics professional to review your personal and family history. Based on the information that you provide, they may be able to help you evaluate the risk that your family has a familial form of GIST and determine whether additional genetic evaluation would be warranted.
If appropriate based on your personal and family history, it may then be recommended that an affected family member (someone who has had GIST) undergo genetic testing to try and determine whether there is a germ-line mutation in the c-kit or PDGFRA gene in the family. Genetic tests are performed on a sample of DNA from blood or saliva. If an alteration were identified in one of these genes, other family members could then undergo genetic testing to determine whether they have also inherited the familial mutation. Only those relatives with the familial mutation would be at increased risk to develop GIST, whereas those who did not inherit the mutation would not share this increased risk.
There are many factors that should be considered before deciding whether to go forward with genetic testing. These can be discussed with a physician, or other genetics professional. To try and locate a genetic counselor in your area, you can go to the website for the National Society of Genetic Counselors and click on the ‘Find a Counselor’ link. However, because so little is known about inherited GIST, most genetic counselors may not know very much about it at first.
Finally, it is important to recognize that genetic testing for familial GIST is imperfect at the present time. It is possible that a family could have a germ-line mutation in c-kit or PDGFRA that would be missed with current testing technology; it is also possible that there are other genes that have not yet been identified that cause some cases of familial GIST. Therefore, even if someone in your family who has had GIST undergoes genetic testing and is not found to have a germ-line mutation in c-kit or PDGFRA, a familial form of GIST could still be present. It is important to understand the current limitations of testing and to work with your physician or a genetics professional to determine the most appropriate medical care for you and your family.
8. If your family has familial GIST, what can you do about it?
There is no uniform set of recommendations about how to follow kindreds with familial GIST.
Individuals who are found to carry a germ-line alteration in the c-kit or PDGFRA gene and who have already been diagnosed with GIST should continue to undergo treatment and monitoring as recommended by their physician.
At the present time, there is no consensus available about the most appropriate screening for individuals with a germ-line alteration in c-kit or PDGFRA who have not developed GIST. Individuals who are identified with a germ-line alteration in one of these genes should consult with their physician to review their personal and family history and determine the most appropriate screening for them. In addition, there is research underway to try and obtain additional information about how best to screen unaffected individuals with germ-line c-kit or PDGFFRA alterations, so we would encourage you to periodically check for updates on this issue.
