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Genetic alterations in the transforming growth factor receptor complex in sporadic endometrial carcinoma
R Nakashima1, H Song, T Enomoto
1Division of Environmental Health Sciences, School of Public Health, College of Medicine and Public Health and the Comprehensive Cancer Center, The Ohio State University, Columbus 43210-1240, USA.
Abstract:
Cellular responses to the transforming growth factor beta (TGFbeta) ligand, including inhibition of cell proliferation, are mediated by a heteromeric receptor complex composed of TGFbeta types I and II receptors (TbetaR-I and TbetaR-II). Loss of responsiveness to TGFbeta, attributed to inactivation of the TbetaR complex, has been implicated in the development of tumors in a number of human epithelial and lymphoid tissues. To gain a better understanding of TGFbeta signal transduction pathways in endometrial carcinogenesis, we have investigated the role of the TbetaR complex by evaluating the TbetaR-I and TbetaR-II genes for mutations throughout the entire coding region in human sporadic endometrial tumors. Using reverse transcription-PCR, "Cold" single-strand conformation polymorphism analysis, and direct DNA sequencing, it was found that 1 of 39 (2.6%) and 7 of 42 samples (17%) contained code-altering changes in the kinase domain of TbetaR-I and TbetaR-II, respectively. In 7betaR-I, a 3-bp deletion was found resulting in replacement of Arg and Glu at codon 237 and 238 by Lys. With TbetaR-II, mutations were found in the kinase, the extracellular, and the C-terminal domains. No frameshift mutations were detected; however, a silent population polymorphism (AAC-->AAT at codon 389) in TbetaR-II was found in 19 of 42 (44%) tumor samples. These results suggest that alteration in TbetaR-II, but not TbetaR-I, has an important role in the development of endometrial carcinoma.
Insights
Transforming growth factor beta (TGFbeta) receptor mutations, particularly in TbetaR-II, are linked to endometrial cancer development. These alterations in TGFbeta signaling pathways may drive tumor progression in the endometrium.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Cellular responses to transforming growth factor beta (TGFbeta) are crucial and mediated by TGFbeta receptor complexes (TbetaR-I and TbetaR-II).
- Loss of TGFbeta responsiveness due to TbetaR complex inactivation is implicated in various human tumors.
Purpose of the Study:
- To investigate the role of TbetaR-I and TbetaR-II gene mutations in endometrial carcinogenesis.
- To understand TGFbeta signal transduction pathway alterations in endometrial cancer.
Main Methods:
- Analysis of TbetaR-I and TbetaR-II coding regions in human sporadic endometrial tumors.
- Utilized reverse transcription-PCR, single-strand conformation polymorphism analysis, and direct DNA sequencing.
Main Results:
- Code-altering changes were found in 2.6% of TbetaR-I and 17% of TbetaR-II kinase domains.
- Mutations in TbetaR-II were identified across kinase, extracellular, and C-terminal domains.
- A silent polymorphism in TbetaR-II was observed in 44% of samples.
Conclusions:
- Alterations in TbetaR-II, not TbetaR-I, play a significant role in endometrial carcinoma development.
- TbetaR-II mutations are implicated in the pathogenesis of endometrial cancer.