title: No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma.
abstract: Germline mutations of the three succinate dehydrogenase subunits SDHB, SDHC and SDHD have recently been associated with familial pheochromocytoma and paraganglioma. Several reasons make these genes candidate tumor suppressor genes for medullary thyroid carcinoma (MTC): (1) SDHB lies on chromosome 1p, the region known to be deleted most frequently in MTC, (2) MTCs develop from neural crest-derived cells, as do pheochromocytomas and paragangliomas and (3) patients with germline mutations of the Ret-protooncogene develop MTCs as well as pheochromocytomas, indicating a relationship of these tumors on a genetic level. Therefore, we attempted to determine whether the tumor suppressor genes SDHB, SDHC and SDHD are involved in sporadic and familial MTC. Somatic mutations of the SDH subunits were absent in all 35 investigated MTCs. Loss of heterozygosity was found in 27% (SDHB) and 4% (SDHD) respectively. While the frequency of non-coding, intronic polymorphisms did not differ in MTC patients compared with a control population, an accumulation of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R in SDHD) was found among MTC patients especially patients with familial tumors, suggesting a functional connection of coding SDH polymorphisms to activating Ret mutations.
authors.affiliation: Institute for Clinical Pathology, Department of Pathology, University Hospital Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Montani
authors.forename: A M
authors.initials: AM
authors.lastname: Schmitt
authors.forename: S
authors.initials: S
authors.lastname: Schmid
authors.forename: T
authors.initials: T
authors.lastname: Locher
authors.forename: P
authors.initials: P
authors.lastname: Saremaslani
authors.forename: P U
authors.initials: PU
authors.lastname: Heitz
authors.forename: P
authors.initials: P
authors.lastname: Komminoth
authors.forename: A
authors.initials: A
authors.lastname: Perren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics*; D005260:Female; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D007506:Iron-Sulfur Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; C108096:SDHC protein, human; C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human