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

The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGF beta resistance, we screened the 7 exons of the type II (T beta R-II) TGF beta receptor and the 9 exons of the type I (T beta R-I) TGF beta 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 beta 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 beta R-I, In addition, 7 of 16 cases were heterozygous for a C-->A polymorphism in intron 7 of T beta R-I. Finally, we identified a 9 base pair in-frame germline deletion in exon I of T beta R-I resulting in loss of 3 of 9 sequential alanine residues at the hi-terminus in 6 of 16 cases. Analysis of specimens from case-control studies indicated that carriers of this del(GGC)(3) T beta R-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 TGF beta was diminished. Our results support the notion that diverse alterations in the TGF beta signaling pathway may play a role in the development of cervical cancer. (C) 1999 Wiley-Liss, Inc.