News from the 17th Pediatric and Wildtype GIST Clinic

The 17th Pediatric and Wildtype GIST Clinic was held at the National Institutes of Health in
Bethesda, Maryland on September 25 – 27, 2019. The Clinic was a collaboration amongst
researchers, specialists, patient advocates, patients and family members, with the goal of
furthering the knowledge of SDH-deficient Gastrointestinal Stromal (GIST) tumors in order to
develop more effective therapies. The following is a summary, written by Becky Owens (patient
advocate), of the keynote address given by Dr. Lee Helman at the Clinic kick-off presentation.
In 2008,given the rarity of the disease, Dr. Helman wasn’t sure whether they could find any
patients to attend the first Pediatric and Wildtype GIST Clinic. He recalled the emotions evident
amongst the 12 patients and family members who attended the first Clinic, as they realized that
they weren’t the only ones in the world with the disease. In the presence of such an ultra-rare
disease, it’s a very therapeutic thing to connect with others in a similar situation. Subsequently,
the Clinic has continued to be held on an annual or semi-annual basis every year.

What have they learned as a result of the Clinic?

The Clinics have allowed researchers to gain a better understanding of how the molecular
characterization of different Wildtype GIST tumor types determines the clinical outcome. In all
but one case, the primary tumor initially developed on the stomach. Frequently, there was more
than one tumor present at the time of diagnosis. The most frequent location of metastasis was
in the liver. These tumors did not have a mutation in either the KIT or PDGFRa gene, as do
approximately 90% of most GISTs. As a result of what they’ve learned, it is now recommended
that tumor samples from patients without a KIT or a PDGFRa mutation have
immunohistochemical (IHC) staining performed in order to determine the presence or absence
of the SDHB protein. If the sample stains negative (indicating a lack of the SDHB protein), the
tumor can be classified as being SDH-deficient. There are multiple consequences of having a
loss of SDH function, which results in a build up of Succinate within the mitochondria: The
presence of too much Succinate poisons the methylation cycle, resulting in a process known as
hypermethylation, which turns “off” some genes that should be “on”. Elevated Succinate also
poisons the proliohydroxylate enzyme, causing the cells to think that they are aren’t getting
enough oxygen (even though they actually are). This process, called pseudohypoxia,
stimulates blood vessel growth into the tumors. Lastly, the presence of increased Succinate
poisons histone function, changing the way the genes are expressed.

Analysis of the tumor samples of the first 85 Clinic participants revealed that approximately 75%
had a mutation of the Succinate Dehydrogenase (SDH) gene. Eight out of ten of these SDH
mutations were identified as being “germline”, meaning that the mutation was present not only in
just the tumor, but also in every cell of the patient’s body. We have 2 copies of each gene.
Those who develop tumors had, for some unknown reason, lost the second copy of the SDH
gene in the tumor cells. Patients with a germline mutation can potentially pass the gene on to
their offspring. There was a 60% female vs. 40% male prevalence pattern in the GIST Clinic
with SDH mutations. Genetic counselling is indicated for family members of patient’s whose
GIST tumor has occurred as the result of an SDH germline gene mutation. The NF1 gene has
also been identified as a an inherited germline mutation that can cause GIST.
The majority of the remaining 25% of the Clinic participants demonstrated a dysfunction of the
SDH gene complex without an identiable SDH gene mutation. Epimutant GISTs are not caused
by a coding sequence alteration, but rather by an alteration in the environment outside of the
DNA. These patients can be described as being “epimutant”. In such cases, SDHC function is
shut off by a process called methylation. These patients are typically younger (with an average
age of 15 at the time of diagnosis), and are overwhelmingly female (with a 99% female
predominance). Family members of those with epimutant GIST are not felt to be at risk for tumor
development therefore genetic counselling for family members is not indicated.
SDH-deficient patients, whether mutant of epimutant, should be screened for paragangliomas,
which have been noted to occur in about 33% of the Clinic participants. The median age for
development of the paragangliomas was approximately 40 years of age, so awareness should
be maintained that they can  occur later in life. A paper recently published in the U.K.
recommended the following guidelines for children with inherited SDH mutations: Those with
SDHB mutations should begin being screened (physical examination and blood draw looking for
markers of paragangliomas) beginning as early as age 5; with full body MRI screening
commencing at age 10. Physicals and lab work should be initiated for those with SDHA, C, or D
mutations at age 10; with full body MRI screening commencing at age 15. Early detection of
paragangliomas is important as paragangliomas often occur singly, and early surgical removal
can be curative.

Future directions

Further study is needed to understand how specific SDH mutations and
epimutations will predict how a patients tumors will behave. SDH-deficient GIST tumors don’t
respond to Gleevec; though it is felt that Sutent and Regorafanib most likely slow tumor growth
due to inhibition of the VEGF pathway. SDH-deficient mouse models and cell lines are needed
which could help to be predictive of the effectiveness of a therapy before trying it on patients.
There is a cell line available that has an SDH plus a RAS mutation; however, the presence of
the RAS mutation could influence the results. They’ve had a hard time growing single-mutation
SDH-deficient GIST and paraganglioma cells and are trying really hard to do so.
Current trials: There are currently 2 open trials for SDH-deficient GIST. Trials recruiting
patients can be identified by typing “SDH-deficient” into the search criteria box at the
www.clinicaltrials.gov website.  A trial using Temozolomide (Temodar) for SDH-deficient GIST is
recruiting patients at UC San Diego. The Guadecitabine trial at NIH has just enrolled their last
GIST patient.  They will release the results once the data is analyzed.

In his concluding statements, Dr. Helman expressed his gratitude to the Clinic patients, past
and present, for their participation. Through their help and cooperation, much has been learned
about the biology of SDH-deficient GIST. The researchers and specialists involved with the
Clinic are working diligently to apply this knowledge in order to develop better therapies.