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Published on: February 24, 2015
Aberrant DNA methylation in lung cancer: biological and clinical implications
Sabine Zöchbauer-Müller1, John D Minna, Adi F Gazdar
1Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria. sabine.zoechbauer@akh-wien.ac.at
Abstract:
Genetic abnormalities of proto-oncogenes and tumor suppressor genes are well-known changes that are frequently involved in lung cancer pathogenesis. However, another mechanism for inactivation of tumor suppressor genes is coming more and more into focus. Epigenetic inactivation of certain tumor suppressor genes by aberrant promoter methylation is frequently observed in lung carcinomas and seems to play an important role in the pathogenesis of this tumor type. While genetic abnormalities are associated with changes in DNA sequence, epigenetic events may lead to changes in gene expression that occur without changes in DNA sequence. Recent findings demonstrate that aberrant methylation can also be detected in the smoking-damaged bronchial epithelium from cancer-free heavy smokers, suggesting that aberrant methylation might be an ideal candidate biomarker for lung cancer risk assessment and monitoring of chemoprevention trials. Moreover, in vitro studies demonstrate that methylation can be reversed by demethylating agents resulting in gene re-expression. This concept is currently under investigation in clinical trials. In summary, recent studies demonstrate that aberrant methylation may be the most common mechanism of inactivating cancer-related genes in lung cancer, occurs already in smoking-damaged bronchial epithelium from cancer-free individuals, can be reversed in vitro by demethylating agents, and may be a useful biomarker for lung cancer risk assessment.
Insights
Aberrant DNA methylation is a common cause of tumor suppressor gene inactivation in lung cancer. This epigenetic change, detectable in smokers, may serve as a lung cancer biomarker and is reversible with treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Genetic mutations in proto-oncogenes and tumor suppressor genes are key in lung cancer.
- Epigenetic alterations, specifically aberrant promoter methylation, are increasingly recognized as critical in lung cancer pathogenesis.
- Unlike genetic changes, epigenetic events alter gene expression without changing the DNA sequence.
Purpose of the Study:
- To investigate the role of aberrant promoter methylation in lung cancer development.
- To assess the potential of aberrant methylation as a biomarker for lung cancer risk.
- To explore the reversibility of epigenetic silencing in lung cancer-related genes.
Main Methods:
- Analysis of aberrant promoter methylation in lung carcinoma tissues.
- Detection of aberrant methylation in bronchial epithelium of cancer-free smokers.
- In vitro studies using demethylating agents to assess gene re-expression.
Main Results:
- Aberrant methylation is a frequent mechanism for inactivating tumor suppressor genes in lung cancer.
- Aberrant methylation is present in the bronchial epithelium of heavy smokers, even in the absence of cancer.
- Demethylating agents can reverse methylation in vitro, leading to the re-expression of silenced genes.
Conclusions:
- Aberrant DNA methylation is a prevalent mechanism for cancer-related gene inactivation in lung cancer.
- Aberrant methylation in bronchial epithelium may serve as an early biomarker for lung cancer risk.
- The reversibility of aberrant methylation suggests potential therapeutic strategies for lung cancer prevention and treatment.
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