BIOCHEMISTRY OF HUMAN PARAGANGLIOMA

We have become interested in the peculiar human tumor called paraganglioma. These unusual tumors form from neuroendocrine tissue in the adrenals, abdomen or carotid bodies. Strangely, a genetic predisposition to paraganglioma results when a patient inherits genes encoding defects in subunits of the metabolic enzyme succinate dehydrogenase. This enzyme is part of the Krebs cycle in central metabolism.

For unknown reasons, loss of both copies of any of three genes encoding succinate dehydrogenase subunits causes tumors in neuroendocrine tissue. It is unprecedented that a defect in a metabolic enzyme should cause tumor growth. Paraganglioma tumors can secrete hormones causing blood pressure problems, or can become malignant and spread in the body as other cancers. We are exploring the use of yeast and mouse models of the predisposing genes of paraganglioma to better understand these most unusual tumors.

Predicted structure of the yeast succinate dehydrogenase complex