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[Cancer Research 60, 6822-6825, December 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Somatic and Occult Germ-line Mutations in SDHD, a Mitochondrial Complex II Gene, in Nonfamilial Pheochromocytoma1

Oliver Gimm, Mary Armanios, Heather Dziema, Hartmut P. H. Neumann and Charis Eng2

Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210 [O. G., M. A., H. D., C. E.]; Medizinische Universitätsklinik, Albert-Ludwigs-Universität, D79106 Freiburg, Germany [H. P. H. N.]; and Cancer Research Campaign, Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, United Kingdom [C. E.]

Most pheochromocytomas are sporadic but about 10% are thought to be hereditary. Although the etiology of most inherited pheochromocytoma is well known, little is known about the etiology of the more common sporadic tumor. Recently, germ-line mutations of SDHD, a mitochondrial complex II gene, were found in patients with hereditary paraganglioma. We sought to determine whether SDHD plays a role in the development of sporadic pheochromocytomas and performed a mutation and deletion analysis of SDHD. Among 18 samples, we identified 4 heterozygous sequence variants (3 germ-line, 1 somatic). One germ-line SDHD mutation IVS1+2T>G (absent among 78 control alleles) is predicted to cause aberrant splicing. On reinvestigation, this patient was found to have a tumor of the carotid body, which was likely a paraganglioma. Another patient with malignant, extra-adrenal pheochromocytoma was found to have germ-line c.34G>A (G12S). However, this sequence variant was also found in 1 of 78 control alleles. The third, germ-line nonsense mutation R38X was found in a patient with extra-adrenal pheochromocytoma. The only somatic heterozygous mutation, c.242C>T (P81L), has been found in the germ line of two families with hereditary paraganglioma and is conserved among four eukaryotic multicellular organisms. Hence, this mutation is most likely of functional significance too. Overall, loss of heterozygosity in at least one of the two markers flanking SDHD was found in 13 tumors (72%). All of the tumors that already harbored intragenic SDHD mutations, whether germ-line or somatic, also had loss of heterozygosity. Our results indicate that SDHD plays a role in the pathogenesis of pheochromocytoma. Given the minimum estimated germ-line SDHD mutation frequency of 11% (maximum estimate up to 17%) in this set of apparently sporadic pheochromocytoma cases and if these data can be replicated in other populations, our observations might suggest that all such patients be considered for SDHD mutation analysis.




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