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

Taiping Chen, E. G.E. De Vries, H. Hollema, H. A. Yegen, V. F. Vellucci, H. D. Strickler, A. Hildesheim, M. Reiss

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Abstract

The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-β (TGFβ)mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGFβ resistance, we screened the 7 exons of the type II (TβR-II) TGFβ receptor and the 9 exons of the type I (TβR-I) TGFβ 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 TβR-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 TβR-I. In addition, 7 of 16 cases were heterozygous for a G→A polymorphism in intron 7 of TβR-I. Finally, we identified a 9 base pair in-frame germline deletion in exon I of TβR-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 TβR-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 TGFβ was diminished. Our results support the notion that diverse alterations in the TGFβ signaling pathway may play a role in the development of cervical cancer.

Original languageEnglish (US)
Pages (from-to)43-51
Number of pages9
JournalInternational Journal of Cancer
Volume82
Issue number1
DOIs
StatePublished - Jul 2 1999

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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