Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma

Int J Cancer. 1999 Jul 2;82(1):43-51. doi: 10.1002/(sici)1097-0215(19990702)82:1<43::aid-ijc9>;2-0.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Cervical Intraepithelial Neoplasia / genetics
  • Female
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Receptors, Transforming Growth Factor beta / genetics*
  • Trinucleotide Repeats
  • Uterine Cervical Neoplasms / genetics*


  • Receptors, Transforming Growth Factor beta