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Loss of transforming growth factor-beta type II receptor gene expression in primary human esophageal cancer
L Garrigue-Antar1, R F Souza, V F Vellucci
1Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
Abstract:
Cell lines derived from carcinomas of the upper aero-digestive tract are typically refractory to transforming growth factor beta-mediated cell cycle arrest. Recently, we reported that the type II transforming growth factor beta receptor (T beta R-II) gene can be inactivated on the basis of missense mutations in such cell lines. These findings prompted us to investigate the molecular status of the T beta R-II gene in primary tumor specimens. Among 21 of 24 evaluable primary esophageal carcinomas, there were 6 cases (28.5%; 95% confidence interval, 11% to 52%) in which T beta R-II transcripts were low or undetectable by a reverse transcription PCR assay. In one of these cases, we were able to ascribe the loss of T beta R-II gene expression to high-density methylation of promoter sequences. We failed to detect any mutations within the open reading frame of the remaining tumors that expressed T beta R-II mRNA. In this relatively small series of cases, loss of T beta R-II expression was independent of pathologic tumor stage, histologic subtype, or outcome of patients with esophageal cancer. Thus, loss of expression of the T beta R-II gene appears to be the predominant mechanism through which this gene is inactivated in esophageal cancer.
Insights
Loss of the transforming growth factor beta receptor type II (TβR-II) gene expression is common in esophageal cancer. This inactivation, primarily through reduced expression rather than mutation, impacts cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Carcinomas of the upper aero-digestive tract often resist transforming growth factor beta (TGF-β)-induced cell cycle arrest.
- Previous work identified missense mutations inactivating the TGF-β receptor type II (TβR-II) gene in cell lines.
Purpose of the Study:
- To investigate the molecular status of the TβR-II gene in primary esophageal tumors.
- To determine the frequency and mechanisms of TβR-II gene inactivation in esophageal cancer.
Main Methods:
- Analysis of TβR-II gene expression in primary esophageal carcinomas using reverse transcription PCR.
- Investigation of promoter methylation as a mechanism for gene silencing.
- Mutation analysis of the TβR-II open reading frame.
Main Results:
- Reduced or undetectable TβR-II transcripts were found in 28.5% of primary esophageal carcinomas.
- Loss of TβR-II expression was linked to promoter methylation in one case.
- No mutations were detected in the TβR-II open reading frame of tumors expressing the mRNA.
- Loss of TβR-II expression was not associated with tumor stage, subtype, or patient outcome.
Conclusions:
- Loss of TβR-II gene expression, rather than mutation, is the predominant mechanism of TβR-II inactivation in esophageal cancer.
- These findings highlight the role of TβR-II dysregulation in esophageal tumorigenesis.