title: Genetic alterations in the transforming growth factor receptor complex in sporadic endometrial carcinoma.
abstract: Cellular responses to the transforming growth factor beta (TGFbeta) ligand, including inhibition of cell proliferation, are mediated by a heteromeric receptor complex composed of TGFbeta types I and II receptors (TbetaR-I and TbetaR-II). Loss of responsiveness to TGFbeta, attributed to inactivation of the TbetaR complex, has been implicated in the development of tumors in a number of human epithelial and lymphoid tissues. To gain a better understanding of TGFbeta signal transduction pathways in endometrial carcinogenesis, we have investigated the role of the TbetaR complex by evaluating the TbetaR-I and TbetaR-II genes for mutations throughout the entire coding region in human sporadic endometrial tumors. Using reverse transcription-PCR, "Cold" single-strand conformation polymorphism analysis, and direct DNA sequencing, it was found that 1 of 39 (2.6%) and 7 of 42 samples (17%) contained code-altering changes in the kinase domain of TbetaR-I and TbetaR-II, respectively. In 7betaR-I, a 3-bp deletion was found resulting in replacement of Arg and Glu at codon 237 and 238 by Lys. With TbetaR-II, mutations were found in the kinase, the extracellular, and the C-terminal domains. No frameshift mutations were detected; however, a silent population polymorphism (AAC-->AAT at codon 389) in TbetaR-II was found in 19 of 42 (44%) tumor samples. These results suggest that alteration in TbetaR-II, but not TbetaR-I, has an important role in the development of endometrial carcinoma.
authors.affiliation: Division of Environmental Health Sciences, School of Public Health, College of Medicine and Public Health and the Comprehensive Cancer Center, The Ohio State University, Columbus 43210-1240, USA.
authors.forename: R
authors.initials: R
authors.lastname: Nakashima
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.forename: T
authors.initials: T
authors.lastname: Enomoto
authors.forename: Y
authors.initials: Y
authors.lastname: Murata
authors.forename: M R
authors.initials: MR
authors.lastname: McClaid
authors.forename: B C
authors.initials: BC
authors.lastname: Casto
authors.forename: C M
authors.initials: CM
authors.lastname: Weghorst
mesh_terms: D030201:Activin Receptors, Type I; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II