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Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma
T Chen1, E G de Vries, H Hollema
1Section of Medical Oncology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8032, USA.
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.
Insights
Transforming growth factor-beta (TGFbeta) resistance is linked to cervical cancer progression. Mutations in TGFbeta receptors (TbetaR-II and TbetaR-I) were identified, with a TbetaR-I variant potentially increasing cervical cancer risk.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Invasive cervical carcinomas often exhibit reduced sensitivity to transforming growth factor-beta (TGFbeta)-mediated cell cycle arrest.
- Understanding the molecular mechanisms behind TGFbeta resistance is crucial for identifying cancer development pathways.
Purpose of the Study:
- To investigate mutations in TGFbeta receptor genes (TbetaR-II and TbetaR-I) in primary invasive cervical carcinoma specimens.
- To explore the association between identified genetic alterations and cervical cancer risk and TGFbeta response.
Main Methods:
- Screening of TbetaR-II and TbetaR-I genes for mutations in 16 paraffin-embedded cervical carcinoma samples.
- Analysis of a germline deletion in TbetaR-I exon 1 for association with cervical cancer risk using case-control studies.
- Assessment of TGFbeta response in cells expressing the variant TbetaR-I receptor.
Main Results:
- A novel mutation in TbetaR-II (E142Stop) leading to a truncated receptor was found in one carcinoma.
- A silent mutation in TbetaR-I exon 6 and a common polymorphism in TbetaR-I intron 7 were observed.
- A 9 base pair deletion in TbetaR-I exon 1 (del(GGC)3) was identified in 6 of 16 cases, associated with diminished TGFbeta response and potentially increased cervical cancer risk.
Conclusions:
- Alterations in the TGFbeta signaling pathway, including mutations in TbetaR-II and TbetaR-I, are implicated in cervical cancer development.
- A specific TbetaR-I germline deletion variant may confer an increased risk for cervical carcinoma.
- These findings highlight the role of TGFbeta pathway dysregulation in oncogenesis.