Program: The Genetics of Paraganglioma 
DCS-project UL 2002-2723


Mechanism of Tumorigenesis of Hereditary Paragangliomas of the Head and Neck


Non-chromaffin paragangliomas are mostly benign and slow-growing tumors of the extra-adrenal paraganglion system in the head and neck region. The tumors usually develop at the carotid bifurcation from the carotid body (CB), which has a chemoreceptor function and monitors the O2 and CO2 concentration in the blood stream. Their incidence in the population is low, but we have found that a substantial proportion is caused by mutations in the SDHD gene on the long arm of chromosome 11. The SDHD gene encodes one of the membrane anchor subunits of mitochondrial respiratory chain complex II (succinate: ubiquinone oxidoreductase) and acts as a tumor-suppressor. SDHD mutations also give a predisposition for adrenal and extra-adrenal pheochromocytomas. The non-Mendelian inheritance pattern suggests that genomic imprinting regulates the expression of the SDHD gene. Our hypothesis is that SDHD mutations mimick a chronic hypoxic situation, which is known to interfere with carotid body maturation and leads to CB hyperplasia. Complex II membrane anchor malfunction probably increases free radical formation, leading to the accumulation of DNA damage. Subsequently, growth-promoting mutations may occur and stimulate clonal outgrowth of tumor cells. The purpose of this project is:

  1. To identify the mechanism by which mutations in the SDHD gene cause hereditary head and neck paragangliomas (HN-paragangliomas), adrenal and extra-adrenal pheochromocytomas
  2. To elucidate the mechanism of imprinting at the SDHD locus
  3. To identify other genetic or environmental factors underlying the development of paragangliomas.

Plan of investigation

Our approach will combine research on human material derived from selected paraganglioma patients and normal individuals, and analysis of Sdhd knockout mouse models.

  1. Human studies. To identify factors involved in paraganglioma development, the gene expression pattern in paragangliomas from patients with or without SDHD mutations will be determined by hybridization to DNA chips and micro-arrays. In addition, we are developing a tissue array containing paragangliomas from patients with or without SDHD mutations and paraganglion tissue from normal individuals. Sections from this tissue array will be analyzed with specific antibodies to confirm the changes in gene expression observed in the DNA chip and micro-array experiments. Furthermore we will screen for the presence of somatic SDHD mutations, which are predicted to occur in at least a small proportion of sporadic HN-paragangliomas with similar genotypic and phenotypic features as typical SDHD-linked tumors (morphology, immuno-phenotype, LOH-patterns).
  2. Mouse studies. We are developing an SDHD knockout model in our laboratory, carrying an allele in which exon 3 has been replaced by an IRES-▀geo cassette. This will allow us to study:

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