title: Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas.
abstract: Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Syney, NSW, Australia.
authors.forename: Diana E
authors.initials: DE
authors.lastname: Benn
authors.forename: Michael S
authors.initials: MS
authors.lastname: Croxson
authors.forename: Kathy
authors.initials: K
authors.lastname: Tucker
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bambach
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Richardson
authors.forename: Leigh
authors.initials: L
authors.lastname: Delbridge
authors.forename: Peter T
authors.initials: PT
authors.lastname: Pullan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hammond
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D001315:Australia / Q000453:epidemiology; D002648:Child; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D042963:Electron Transport Complex II; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D007506:Iron-Sulfur Proteins; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D009377:Multiple Endocrine Neoplasia / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009386:Neoplastic Syndromes, Hereditary / Q000201:enzymology / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics; D010235:Paraganglioma / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D010673:Pheochromocytoma / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D022821:RNA Splice Sites / Q000235:genetics; D012186:Retroperitoneal Neoplasms / Q000201:enzymology / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
chemical_list: D004273:DNA, Neoplasm; D007506:Iron-Sulfur Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D021122:Protein Subunits; D022821:RNA Splice Sites; D010088:Oxidoreductases; D042963:Electron Transport Complex II; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase