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Analysis of the SDHD Gene, the Susceptibility Gene for Familial Paraganglioma Syndrome (PGL1), in Pheochromocytomas¹

Departments of Adult Oncology (R.C.T.A., P.L.M.D.) and Cancer Biology (P.L.M.D.), Dana-Farber Cancer Institute, and Departments of Genetics (G.C.) and Neurology (S.L.P.), Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115-6084

Address all correspondence and requests for reprints to: Patricia L. M. Dahia, Department of Cancer Biology/Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, SM1010, Boston, Massachusetts 02115-6084. E-mail: patricia_dahia{at}dfci.harvard.edu

Abstract

Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739AG). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34–36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.

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