Question and Answer correspondence with 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: firstname.lastname@example.org
Visiting address: Dept. of Human Genetics, Bldg 2, room R-04-022, Einthovenweg 2, 2333 ZC Leiden,