title: Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas.
abstract: Ovarian carcinomas (OCs), particularly recurrent OCs, are frequently resistant to transforming growth factor (TGF)-beta-mediated growth inhibition. Mutations in the TGF-beta receptor type II (TbetaR-II) gene are only evident in a minority of OCs, suggesting that other alterations of the TGF-beta signaling pathway may be involved in OC. Using PCR, cold single-strand conformation polymorphism, and DNA sequencing, we now show that 33% of primary OCs (10 of 30) harbor somatic changes in exons 2, 3, 4, and 6 of the TGF-beta receptor I (TbetaR-I) gene. Most of the changes are missense mutations and clustered largely in the catalytic domain of the receptor kinase. Interestingly, seven additional cases (23.3%) showed heterozygous carriers of an allelic variant [a 9-nucleotide deletion, del(GGC)(3)] in exon 1 of the TbetaR-I gene. This is in contrast with 10.6% of del(GGC)(3) heterozygous carriers in a recent report of a large normal population (n = 735; B. Pasche et al., Cancer Res., 59: 5678-5682, 1999). These results indicate that TbetaR-I is frequently mutated in OC and suggest that resistance to TGF-beta-mediated growth inhibition may frequently involve alterations of the TbetaR-I gene.
authors.affiliation: Wood Hudson Cancer Research Laboratory, Newport, KY 41071-4701, USA. tchen@woodhudson.org
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Triplett
authors.forename: B
authors.initials: B
authors.lastname: Dehner
authors.forename: B
authors.initials: B
authors.lastname: Hurst
authors.forename: B
authors.initials: B
authors.lastname: Colligan
authors.forename: J
authors.initials: J
authors.lastname: Pemberton
authors.forename: J R
authors.initials: JR
authors.lastname: Graff
authors.forename: J H
authors.initials: JH
authors.lastname: Carter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D005091:Exons; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics*; D016612:Paraffin Embedding; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta