So, I’ve been told that I have GIST!

The 15th Pediatric and Wildtype GIST Clinic was held at the National Institute of Health in Bethesda, Maryland on July 5-7, 2017. The Clinic is a collaborative effort between clinicians and researchers to collect data supporting the investigation and development of treatment for Gastrointestinal Stromal Tumor (GIST) patients who do not have either c-KIT or PDGF mutations. Eleven new patients were seen at this Clinic, bringing the total tally of patient’s evaluated since the clinic’s inception to 163.  Becky Owens attended the meeting as a representative of GIST Support International and has provided the following summary of the keynote address given by Dr. Lee Helman.

The incidence of Pediatric GIST is rare.  As a result, no doctor would typically see a lot of cases. In response to this, we formed a consortium of researchers dedicated to the study of this disease which didn’t appear to be responding to the typical treatments used for GIST.  Though there are still many, as yet, unanswered questions, we have learned a lot since the first Clinic in 2008.  The first major breakthrough occurred In 2011 when it was  learned that mutations in the Succinate Dehydrogenase (SDH) gene were frequently involved in the disease pathogenesis. We then began to learn that there were different molecular subtypes, each one with maybe a slightly different clinical presentation.  We engaged surgeons to better understand the best surgical management.  Ultimately, we desire to identify effective drug management for patients in all of the subtypes, but we aren’t there yet. 

Most of the Clinic patients (with the exception of one) have presented with primary tumors in the stomach. In contrast, the primary tumors of KIT-mutant GIST patients may originate in other locations in the gastrointestinal tract, for example, in the small bowel. In both instances, the most common site of metastasis is the liver.

It has ben identified that 85% of the general GIST population have either KIT or PDGF mutation.  These patients typically respond to Gleevec or Sutent, as these drugs target the mutation driving their tumor growth.  A much smaller percentage (4%) of GISTs, do not have either a KIT or PDGF mutation and are SDH-deficient.  These patients rarely achieve systemic disease control with medication.

We break the SDH-deficient GISTs into two groups: those that have SDH mutations and those that don’t.

SDH mutations can occur in subunit a,b,c, or d.  The vast majority are located a,b, or c—we have only identified one patient with a subunit d mutation.  Approximately 25% of SDH-deficient GISTs don’t have a subunit mutation, but are instead SDHC epimutant.  Of those with an identifiable SDH mutation, the female:male incidence is about 60%:40%.  However, in  SDHC epimutant GIST the incidence is overwhelming female.  The epimutant patients are usually younger, with an average age at original diagnosis of 23 years.

SDH-deficiency is determined by applying immunohistochecal (IHC) stain to the tumor sample.  If you apply this stain to a KIT-mutant GIST tumor, there is plenty of the SDH protein present.  In SDH-mutant GIST, there is an absence of the SDHB protein. However, identifying that a patient is SDH-deficient does not necessarily indicate that a SDH gene mutation is present, only that there is a problem somewhere in the function of the SDH complex.

Statistically, the vast majority of the patients seen in the Clinic are SDH-deficient. Genomic analysis of SDH-deficient tumors reveals that there is a difference in the way they are methylated. Methylation is the regulatory process by which a gene can be turned on or off to generate protein.  It was a remarkable discovery that all of the SDH-deficient tumors were hypermethylated, They looked completely different from the KIT-mutant GIST tumors (which were not hypermethylated).

One of the most interesting things we’ve learned is that most of the SDH mutations occur in the germline—meaning that the mutation can also be found in the structure of  every cell in the patient’s body This does not mean that every cell in the body has the cancer, just the potential. So why do the primary tumors always form in the stomach? We’re not really sure why this happens… It appears that in the tumor, the second allele of the gene has somehow become compromised, damaged, or lost.

We’ve believe that epimutant SDH-deficient patients, without a specific SDH mutation, have a problem with the regulatory element of the SDHC gene that makes it behave as mutant because it doesn’t shut off.  This could be the case with Carney Triad. Although the DNA sequence is not changed in epimutant genes, they are unable to perform normally. Distinguishing between having a mutation or an epimutation has clinical implications for two reasons:

1: For those with an SDH mutation, we need to know if it is a germline or a somatic mutation. If it is germline, you have probably inherited the mutation from one of your parents and genetic counseling is recommended. Your siblings and children have a 50%/50% chance of having also inherited the mutation. Having an SDH mutation can predispose you to getting GIST tumors and paragangliomas, as is the case with Carney-Stratakis Dyad patients.  Those with an SDH germline mutation should be monitored for both GIST and/or paragangliomas.  In most patients, we seem to see the GIST first, so we can monitor for paragangliomas. If paragangliomas develop, they can usually be surgically removed.

We have identified a few Clinic participants who are WT for KIT/PDGF but are not SDH-deficient.  Within this group we have identified mutations in ARID1-A, BRAF, or NF1. NF1-mutant GISTs are usually germline.  It is recommended that they be seen in a neurofibromatosis clinic and also followed by GIST experts.  NF-mutant GIST patients are also at increased risk for paragangliomas and a possiblity for kidney cancer.

2:  For those with with an epimutant SDH problem, such as with Carney Triad, the family does not have to be tested as this is not an inherited problem.  Carney Triad patients are prone to getting GIST tumors, paragangliomas, and pulmonary chondromas; however, their family members are not at increased risk.

When looking at the whole genome with comparative hybridization, most cancer tumors have lots of changes across all their chromosomes and are genetically unstable.  In contrast, when looking at the chromosomes of SDH-deficient tumor cells, they look much more like normal cells.  They don’t need to loose or gain chromosomes in order to survive as they do it through altered methylation instead.

Why would they be methylated?  The mitochondria create energy in every cell by generating ATP.  ATP is made through a series of enzymatic changes, moving from alpha-ketoglutarate to succinate to fumarate, with the SDH gene involved in this last step. Without proper function of the SDH gene, succinate is not converted to fumarate, resulting in an accumulation of succinate. The ratio between alpha-ketoglutarate and succinate affects the ability of the cells to demethylate.  Too much succinate, and not enough alpha-ketoglutarate, globally poisons the DNA demethylation process interfering with the abillity of the cells to actrively demethylate.  The presence of excess succinate also impacts the the enzymatic process involved with angiogenesis involving HIF-1a.  In this case, the cells falsely perceive that they aren’t getting enough oxygen, a condition known as pseudohypoxia.  Pseudohypoxia stimulates increased vascularization and cell proliferation in the tumors.

What else have we learned?  What we do know is that we can’t cure this by surgery because this mutation is in every cell in your body.  It is often multifocal.  Therefore, we usually discourage surgical removal of the the whole stomach, opting for a more minimize approach with less impact on the quality of life. Surgery can be helpful to control bleeding, for obstruction, for symptomatic control, or to get a diagnosis. It has become the emerging opinion of the surgeons involved with the Clinic that obtaining clear margins may not be of as vital importance as with other cancers. In an analysis of the first 70 SDH-deficient Clinic attendees, frequently you had development of a new tumor by 2 1/2 years post-op even if you resected everything.  Unlike with other types of cancers, where if you have a recurrent tumor you have a really bad prognosis, with SDH-deficient GIST, the recurrent disease doesn’t portend a horrible outcome.  For most of SDH-deficient patients, the median survival is very long.  Therefore, we don’t recommend aggressive surgery as there is no evidence that it will control the disease.  The Clinic surgeons recommend only removing a tumor that is causing a problem.  Just because a tumor is present doesn’t necessarily mean we will recommend trying to take it out.

We don’t believe that patients with SDH-deficiency respond to Gleevec.  We still have patients that come to us on Gleevec, but fewer than before.  If the patient is doing well, not progressing, and they are tolerating Gleevec well, we usually don’t recommend discontinuing it.  However, most of the NIH Clinic Specialists feel that Gleevec is probably not doing much. On the other hand, we usually recommend discontinuance of Gleevec to patients that  are experiencing problematic side effects because as there does not seem to be objective evidence that it is effective.  This is in marked contrast to the recommended treatment for KIT or PDGF-mutant GIST patients, where you almost always see some initial response.  With respect to Sutent, we definitely see some response in about 25% of cases.  This may be attributable to Sutent’s anti-angeogenic effect inhibiting blood vessel growth.  We’ve also seen some definite responses  to Stivarga. If a newly diagnosed patient needs to be on a drug, we would probably recommend Sutent first, because it is generally better tolerated than Stivarga.

Where are we headed in terms of treatment?  There is a class of drugs called DNA  demehtyltransferase inhibitors that could demethylate SDH-deficient tumors. These drugs have been used successfully in myelodysplastic syndromes such as pre-leukemia. They work by inhibiting the methylation of a huge number of genes.  There is a newer methyltransferase inhibitor that lasts longer in the bloodstream called SGI-110, or Guadacitabine.  We’ve opened a new study at the NIH to evaluate the efficacy of Guadacitabine in addressing the methylation problem in SDH-deficient GIST.

This drug has been given to hundreds of patients with other cancers now and we know the side effects. It mainly affects the blood count, but most patients tolerate it extremely well. It is our hope that not allowing the genome of SDH-deficient tumors to stay methylated will prove to be a good treatment option.  Presently, the drug is only available subcutaneously, so you would have to be at NIH in Bethesda, Maryland for 5 days in a row every 4 weeks.  If the treatment shows successful activity over time, we are hopeful that the shots could eventually be self administered.

When the Pediatric and WT GIST Clinic was begun in 2008, we weren’t sure if we’d even get 3 patients, but we got 12. Everyone who had this disease felt that they were the only patient with it in the world. Now you know that you are not alone. First, we have to understand it, and then we have to develop treatments. That’s what we’re working really hard to do and that is our hope.  We’re very appreciative to see all of the Clinic patients, because the more we see you, the more we understand.

So, thank you. - Dr. Helman

Patients interested in participating in the NIH Pediatric and WT GIST Clinic may write:  
Claudia.Derse-Anthony@fnlcr.nih.gov

Dr. Jean-Pierre Bayley, The Netherlands, Spring 2017

Q: How do tumors emerge and are external, environmental factors involved?

Bailey: Hereditary tumors emerge following a random, chance event in a single cell through which the last normal copy of the gene is lost. This then creates the conditions in which a tumor develops. Whether this event can be triggered by external factors is unknown, but random genetic mistakes that occur due to normal body processes are currently thought to cause most tumors. “Tumors emerging” is usually preceded by many years of sub-clinical growth at which time a patient is unaware of a tumor. By the time a clinician sees a tumor many years or even decades may have passed since the first onset of the tumor. In terms of carotid body tumors it is worth recalling that the normal organ is the size of a rice grain whereas clinically-apparent tumors may be many hundreds of times larger.

Q: How is SDH-mutated GIST different than c-kit/PDGFR mutated GIST?

Bailey: As far as we know, all GISTs arise from the Interstitial cells of Cajal. However, just as pheochromocytomas have two distinct origins (SDH-related or Kinase-related), GISTs also appear to have two distinct origins (SDH-related or Kinase-related) and the resulting tumors may have little in common except a possibly similar cell of origin. But this is all we know right now.

Q: PPGLs with mutations in SDHB are the most aggressive forms of the disease, partly owing to their pseudo-hypoxic character, metabolic abnormalities, and elevated levels of reactive oxygen species (ROS).

Bailey: These 3 phenomena certainly occur in these tumors but causality of one or more of these phenomena, especially SDHB-related causality, has not yet been shown (impossible without a good model).

Q: Treatment of mouse PHEO cells with resveratrol as well as ATP5B antibody led to statistically significant inhibition of proliferation.

Bailey: The mouse pheo cells used in this study are unrelated to SDH disease. There is, unfortunately, no alternative SDH-related model available at the moment. While ATP5B is expressed on SDHB paragangliomas, the relevance of this treatment for SDH cancer is presently unclear.

Q: 3-Nitropropionic acid (3-NP), a naturally occurring mycotoxin, is an irreversible inhibitor of succinate dehydrogenase that produces adenosine triphosphate (ATP) depletion in cerebral cortical explants and is associated with motor disorders in livestock and humans that have ingested contaminated food.

Bailey: NPA is a useful lab tool but SDH patients have already lost complex II activity. Tumor cells that arise in the paraganglia of SDH patients are unusual in that they can survive without complex II activity. They appear to be one of the few cell types in the body that can, as SDH tumors are confined to only a very small number of organs. Other cells probably die due to loss of complex II, although this has not yet been shown experimentally.

Q: I do want to ask one more question about 3-NP because I was told that our SDHB mutation is fully mutated in the tumor cells. That the rest of our system is one good gene and one bad gene. My question is what can turn that "good" gene into a "bad" one? Thus the toxin 3-NP which any patient could accidentally have eaten or been exposed to in a mold infested environment, could "take out" the "good" SDHB gene and result in tumors? Or a real hypoxia situation?
 

Bailey: A gene is a piece of DNA that mostly makes a protein, the molecules that form much of the structure and do most the work in the body. Genes are often compared to blueprints, and are simply instructions how to make a protein (and sometimes other molecules). Everyone is born with two copies of these "blueprints" (around 20,000 different ones in all), one from your father and one from your mother. This is handy because not all blueprints are perfect. Most of us have errors in some of our blueprints (genes) and sometimes these mistakes cause disease, just as a bad blueprint can cause mistakes when making a machine or building a house. Mostly, the other good gene will make up for the bad one. Just as a builder ordering parts based on two blueprints will always have at least one delivered, even if one of the blueprints has an error, genes make two “parts” that compensate for the risk of an error in one of the gene copies.

Q: How is inherited cancer different?

Bailey: In family cancer, something else tends to happen. You received a gene with a mistake (mutation) from one of your parents but the other parent gave you a gene without a mistake that works just fine. Most of your life you are okay because that one good gene keeps working. The trouble happens when one of the many billions of cells in your body gets into problems and loses that one good gene. In most cases this cell will die and you will be none the wiser and no worse off.
Unfortunately, in some parts of the body this cell can survive (we do not yet know why) and becomes the first cancer cell, starting to make many more cells when it shouldn't. Many different problems can cause that one good gene to be lost. There is no clear link between any external factor and the loss of a good copy of SDHB. If you are thinking about self-treatment with drugs or supplements, I am sorry to say that there is nothing you can do right now and doing things to prevent “loss of SDHB” may result in you harming yourself in some other way. Try to stay as healthy as you can and in a positive frame of mind, if that is possible. 

You can be assured that many scientists are striving to find a way to treat your disease and although it would be giving entirely false hope to say that we are close to an answer, real progress is being made.

Remember that every scientific journey to find a cure is a journey that has a clear destination but at a distance that is unknown. We hope that our destination is just over the next hill, but it might be on the other side of the mountain. But the journey has begun...

Dr Jean-Pierre Bayley 
Paraganglioma Research Group, Department of Human Genetics,
Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
T: +31 71 5269512; F: +31 71 5268285; email: j.p.l.bayley@lumc.nl
Visiting address: Dept. of Human Genetics, Bldg 2, room R-04-022, Einthovenweg 2, 2333 ZC Leiden,
The Netherlands

Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review.