New Findings in the Genetics of Carney-Stratakis Syndrome and Carney Triad

GIST Support International posed questions about pediatric GIST syndromes to Constantine A. Stratakis, MD ScD. Dr. Stratakis is head of the Section on Endocrinology & Genetics at the National Institutes for Child Health and Human Development. Dr. Stratakis is ABP-certified (in Pediatrics), and has sub-specialty certification in Pediatric Endocrinology; Dr. Stratakis is also a Clinical Geneticist, certified by the American Board of Medical Genetics, and his research focuses on Pediatric Cancer Genetics. His clinical interests are wide, but the majority of his work has been spent elucidating the molecular basis of inherited syndromes, analyzing genetic defects at the molecular level.

Recently Dr. Carney, Dr. Stratakis, and numerous colleagues from around the world formed a consortium to pool their tissue samples from patients with Carney Triad and Carney-Stratakis Syndrome and to conduct new analyses. Their efforts have so far resulted in publication of three important new papers listed as References at the end of this piece.

We interviewed Dr. Stratakis by phone to ask questions about the new findings in these papers. As a starter for discussion, we made a table comparing the two syndromes in terms of genetic predisposition and observed abnormalities in succinate dehydrogenase (SDH) gene subunits.

	Carney Triad	Carney-Stratakis Syndrome
GISTs possible?	yes	yes
Paragangliomas possible?	yes	yes
Pulmonary chondromas possible?	yes	no
Familial (heritable)?	no	yes
Gender-related?	mostly female	equal gender occurrence
Mutations in KIT or PDGFRA?	no	no
Mutations in SDH subunits?	no	yes in 9 of 11 families
Chromosomal loss of SDH?	yes in some	yes in some

Here are our questions and what we learned from our conversation with Dr. Stratakis.

1. What are the most important implications of these new findings?

First: It is clear that Carney Triad and Carney-Stratakis syndrome (also called GIST-paraganglioma dyad) are two separate diseases, and neither disease shows mutations in the KIT or PDGFRA genes.

Second: The vast majority of Carney-Stratakis syndrome cases are due to succinate dehydrogenase germline mutations which are heritable (familial), while a portion of Carney Triad patients may have some contribution to their disease from impaired succinate dehydrogenase function resulting from chromosomal losses (not mutations).

Third: These results are the first to link paragangliomas and GISTs to a common familial mutation; therefore,
a.all familial paraganglioma patients should be screened for development of GISTs, and
b.all young wild-type GIST patients should be screened for succinate dehydrogenase abnormalities.

Fourth: This is the first indication that mutation of succinate dehydrogenase subunit C can cause paragangliomas in the abdomen. Previously SDH subunit C mutations had only been associated with head and neck paragangliomas.

Fifth: Targeting succinate dehydrogenase function may potentially be useful in treating Carney-Stratakis syndrome patients and those Carney Triad patients who show SDH deficiencies. Targeting SDH may temper or improve response to tyrosine kinase inhibitors such as imatinib and sunitinib.

2. Do any drugs currently exist to restore succinate dehydrogenase function?

Not really. However, we may have other strategies to manipulate mitochondrial function in relationship to tumorigenesis.

3. How about drugs to inhibit hypoxia-inducible factor 1 alpha? Would those drugs potentially be useful?

Yes, both the SDH pathway and the KIT pathway converge on hypoxia-inducible factor 1 alpha (HIF-1a); therefore, HIF-1a inhibitors might be clinically helpful.

4. At the most basic level, what is the function of succinate dehydrogenase (SDH) in normal cellular metabolism?

SDH is required in the Krebs cycle (also called the citric acid cycle), the mechanism normal cells use to obtain energy from glucose through chemical reactions involving oxygen.

5. What is pseudo-hypoxia and how does it promote cancer?

Tumors cannot grow large without developing new blood vessels to supply them with oxygen and glucose. If the cell is not receiving enough oxygen (a state of hypoxia), then hypoxia-inducible factor 1-alpha is activated, and it triggers VEGF to stimulate blood vessel development. This permits the tumor to grow. “Pseudo-hypoxia” refers to activation of HIF-1a and VEGF in the absence of a true oxygen deficiency. It promotes cancer through angiogenesis and the switch from normal oxygen metabolism to “anaerobic glycolysis” (the Warburg effect).

6. Can pseudo-hypoxia be caused by mutations in any one of the SDH subunits? Can it be caused by loss of the chromosome section containing the SDH genes?

Yes, apparently a mutation in any one of the SDH subunits (called subunits B, C, and D) — or the loss of SDH through chromosome damage — can disrupt the Krebs cycle and result in pseudo-hypoxia.

7. Is mutation of SDH sufficient to cause tumors, or is it a promoting condition requiring additional events to start a tumor?

In a familial germline mutation, the person inherits one mutant copy of the SDH subunit gene and one normal copy. Germline mutation of a SDH subunit gene predisposes the affected individual to develop GISTs and paragangliomas, but tumors do not occur unless the normal copy is also lost in a cell, initiating a tumor.

8. Does the absence of SDH defects in two Carney-Stratakis Syndrome families indicate that there is another so-far unidentified contributing cause?

No, it is common for 10-30% of persons genetically tested for a given syndrome not to be found positive for the causative mutation. Examples include such genetic disorders as neurofibromatosis, tuberous sclerosis, multiple endocrine neoplasia type-1 and another disorder described by Dr. Carney, Carney complex. Therefore the failure to detect SDH mutations in 2 of 11 families studied does not necessarily mean that SDH defects are not the cause in all of the patients with Carney-Stratakis syndrome.

9. Your consortium identified some unaffected carriers of mutant SDH genes in the Carney-Stratakis syndrome families. Therefore, is it possible that more of the original Triad cases with only 2 tumor types present (that is, patients who do not show chondromas) may be found to have Carney-Stratakis syndrome instead?

Yes, this is possible. Such patients should be tested for SDH mutations.

10. Should pediatric GIST patients seek genetic testing to determine if SDH defects may be contributing to their tumor growth or recurrence?

Yes. Many labs can perform this testing.

11. What is the international Carney Triad and Carney-Stratakis syndrome consortium? Please explain its funding sources and goals. Is additiona
l work still continuing?

The consortium was created ad hoc for the identification of the genetic defects in these conditions. It essentially describes the collaboration between Dr. Carney (Mayo Clinic) and NIH Laboratories with investigators at the Cleveland Clinic (Dr. Eng; formerly at Ohio State University), in France and Italy. The main funding is through grants to Dr. Stratakis and a 2007 NIH Clinical Center Bench-to-Bedside Award to Dr. Stratakis and Dr. Eng co-sponsored by the National Institute of Child Health & Human Development (NICHD) and the Office of Rare Diseases (ORD). The individual investigators participating in the consortium have received funding through their respective funding agencies, also, part of which is also used for this work. We continue to investigate these diseases.

References (click title for link in PubMed)

Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA.
Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.
Eur J Hum Genet. 2007 Aug 1; [Epub ahead of print]
PMID: 17667967

Matyakhina L, Bei TA, McWhinney SR, Pasini B, Cameron S, Gunawan B, Stergiopoulos SG, Boikos S, Muchow M, Dutra A, Pak E, Campo E, Cid MC, Gomez F, Gaillard RC, Assie G, Fuzesi L, Baysal BE, Eng C, Carney JA, Stratakis CA.
Genetics of Carney Triad: Recurrent Losses at Chromosome 1 but Lack of Germline Mutations in Genes Associated with Paragangliomas and Gastrointestinal Stromal Tumors.
J Clin Endocrinol Metab. 2007 Aug;92(8):2938-2943.
PMID: 17535989

McWhinney SR, Pasini B, Stratakis CA; International Carney Triad and
Carney-Stratakis Syndrome Consortium.
Familial gastrointestinal stromal tumors and germ-line mutations.
N Engl J Med. 2007 Sep 6;357(10):1054-6. No abstract available.
PMID: 17804857