title: Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma.
abstract: The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-beta (TGFbeta)-mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGFbeta resistance, we screened the 7 exons of the type II (TbetaR-II) TGFbeta receptor and the 9 exons of the type I (TbetaR-I) TGFbeta receptor genes for mutations in 16 paraffin-embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G-->T transversion in exon 3 of TbetaR-II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor. In one tumor, a silent A-->C transversion mutation that may affect mRNA splicing was present in exon 6 of TbetaR-I. In addition, 7 of 16 cases were heterozygous for a G-->A polymorphism in intron 7 of TbetaR-I. Finally, we identified a 9 base pair in-frame germline deletion in exon 1 of TbetaR-I resulting in loss of 3 of 9 sequential alanine residues at the N-terminus in 6 of 16 cases. Analysis of specimens from case-control studies indicated that carriers of this del(GGC)3 TbetaR-I variant allele may be at a increased risk for the development of cervical carcinoma (p=0.22). Furthermore, the response of cells expressing the variant receptor to TGFbeta was diminished. Our results support the notion that diverse alterations in the TGFbeta signaling pathway may play a role in the development of cervical cancer.
authors.affiliation: Section of Medical Oncology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8032, USA.
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: H
authors.initials: H
authors.lastname: Hollema
authors.forename: H A
authors.initials: HA
authors.lastname: Yegen
authors.forename: V F
authors.initials: VF
authors.lastname: Vellucci
authors.forename: H D
authors.initials: HD
authors.lastname: Strickler
authors.forename: A
authors.initials: A
authors.lastname: Hildesheim
authors.forename: M
authors.initials: M
authors.lastname: Reiss
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D005260:Female; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D018911:Trinucleotide Repeats; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D002578:Uterine Cervical Dysplasia / Q000235:genetics
chemical_list: D018125:Receptors, Transforming Growth Factor beta