Human Molecular Genetics Advance Access published online on March 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi092
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1 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Thoracic and Cardiovascular Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
* To whom correspondence should be addressed. Genome-wide screening of DNA copy-number aberrations in 27 cell lines derived from non-small cell lung cancers (NSCLCs), using a custom-made comparative genomic hybridization (CGH)-array, identified a homozygous deletion of the Deleted in Bladder Cancer 1 gene (DBC1) in one cell line. Homozygous deletion of DBC1, located at 9q33.1, was also observed in two of 53 primary NSCLC tumors examined. Moreover, 21 of the other 26 cell lines showed complete loss of DBC1 expression, although normal lung tissues express this gene, and treatment with 5-aza-2'-deoxycytidine restored expression of DBC1 . Hypermethylation in part of a CpG island around the exon 1 of DBC1 has been reported in urothelial cancers, but the potential association between methylation and expression status was never clarified in that disease. In our experiments, a different part of the same CpG island showed promoter activity in vitro and was frequently methylated in our cell lines and primary tumors of NSCLC, where methylation status correlated inversely with gene expression. Among our primary NSCLC cases, methylation of the DBC1 promoter occurred more frequently in men, elderly patients, and smokers than in women, younger patients, and non-smokers respectively, but it was not correlated with tumor stage or histology. Exogenous over-expression of DBC1 in NSCLC cell lines lacking its expression inhibited cell growth. Our results provide the first evidence that DBC1 is a likely tumor suppressor for NSCLC; silencing of the gene through homozygous deletion or methylation of its promoter region may be associated with progression of this disease.
Article
Frequent Silencing of DBC1 is by Genetic or Epigenetic Mechanisms in Non-Small Cell Lung Cancers
2 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Saitama 332-0012, Japan
3 Tokyo Kyosai Hospital, Tokyo 153-8934, Japan
4 Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
5 Thoracic and Cardiovascular Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
6 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Center of Excellence program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Saitama 332-0012, Japan
Johji Inazawa, E-mail: johinaz.cgen{at}mri.tmd.ac.jp
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