Aberrant DNA methylation in lung cancer: biological and clinical implications.
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.
Zöchbauer-Müller
Sabine
S
Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria. sabine.zoechbauer@akh-wien.ac.at
Minna
John D
JD
Gazdar
Adi F
AF
D014408:Biomarkers, Tumor / Q000032:analysis; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D012907:Smoking / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism; D013183:Sputum / Q000378:metabolism
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm