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

✍ Scribed by Taiping Chen; E.G.E de Vries; H. Hollema; H.A. Yegen; V.F. Vellucci; H.D. Strickler; A. Hildesheim; M. Reiss

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: French
• Weight: 312 KB
• Volume: 82
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19990702)82:1<43::aid-ijc9>3.0.co;2-0

✦ Synopsis

The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-␤ (TGF␤)mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGF␤ resistance, we screened the 7 exons of the type II (T␤R-II) TGF␤ receptor and the 9 exons of the type I (T␤R-I) TGF␤ 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 T␤R-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 T␤R-I. In addition, 7 of 16 cases were heterozygous for a G=A polymorphism in intron 7 of T␤R-I. Finally, we identified a 9 base pair in-frame germline deletion in exon 1 of T␤R-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 T␤R-I variant allele may be at a increased risk for the development of cervical carcinoma (p‫.)22.0؍‬ Furthermore, the response of cells expressing the variant receptor to TGF␤ was diminished. Our results support the notion that diverse alterations in the TGF␤ signaling pathway may play a role in the development of cervical cancer.