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SDHA is a tumor suppressor gene causing paraganglioma
Nelly Burnichon1, Jean-Jacques Brière, Rossella Libé
1Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, 20-40 rue Leblanc, F-75015 Paris, France. nelly.burnichon@inserm.fr
Human Molecular Genetics
|May 21, 2010
Summary
A novel SDHA gene mutation causes paraganglioma and pheochromocytoma by inducing pseudo-hypoxia. This finding adds SDHA to the list of tumor suppressor genes linked to these rare neuroendocrine tumors.
Area of Science:
- Biochemistry
- Oncology
- Genetics
Background:
- Hereditary paragangliomas and pheochromocytomas are linked to mutations in SDHB, SDHC, SDHD, and SDHAF2.
- The role of SDHA in this syndrome was previously unestablished.
Observation:
- A patient with a catecholamine-secreting abdominal paraganglioma harbored a heterozygous germline SDHA mutation (p.Arg589Trp).
- Functional studies in yeast and tumor tissue revealed loss of succinate dehydrogenase enzymatic activity.
- Immunohistochemistry and transcriptome analysis indicated that the SDHA mutation induces pseudo-hypoxia, increasing angiogenesis.
Findings:
- The identified SDHA mutation leads to loss of enzymatic function.
- SDHA mutations can cause pseudo-hypoxia and increased angiogenesis, similar to other SDHx mutations.
- Loss of heterozygosity at the SDHA locus was observed in the patient's tumor.
Implications:
- The SDHA gene should be recognized as a tumor suppressor gene involved in the tricarboxylic acid cycle.
- SDHA is a newly identified susceptibility gene for paraganglioma and pheochromocytoma.
- This discovery expands the genetic landscape of neuroendocrine tumor predisposition.
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