Human Molecular Genetics Advance Access originally published online on May 12, 2006
Human Molecular Genetics 2006 15(13):2038-2044; doi:10.1093/hmg/ddl128
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Frequent genetic and epigenetic abnormalities contribute to the deregulation of cytoglobin in non-small cell lung cancer
1 University of Liverpool Cancer Research Centre, Roy Castle Lung Cancer Research Programme, 200 London Road, Liverpool L3 9TA, UK and 2 Molecular Genetics and Oncology Group, School of Dental Sciences, University of Liverpool, Liverpool L69 3BX, UK
* To whom correspondence should be addressed. Tel: +44 1517948920; fax: +44 1517948989; Email: liloglout{at}roycastle.liv.ac.uk
Received March 9, 2006; Revised May 3, 2006; Accepted May 10, 2006
Lung cancer demonstrates the highest mortality in the UK. Previous studies have implicated allelic loss at chromosome 17q in the development of non-small cell lung carcinoma (NSCLC), and a number of known and putative tumour-suppressor genes reside within this region. One candidate tumour-suppressor gene is cytoglobin (CYGB), which is contained entirely within the 42.5 kb tylosis with oesophageal cancer (TOC) minimal region. CYGB abnormalities have been demonstrated only in sporadic head and neck cancers. In this study, we investigated the expression, promoter methylation and allelic imbalance status of this gene in 52 paired (normal/tumour) surgically excised lung tissue samples from patients with NSCLC. CYGB expression in tumour tissue was significantly reduced compared with corresponding adjacent normal in 54% of the examined cases (paired t-test, P<0.001). The CYGB promoter was shown by pyrosequencing to be significantly hypermethylated [2-fold increase of methylation index (MtI) in tumours] in 25/52 (48%) tumour samples compared with normal samples. MtI of the CYGB promoter was associated with CYGB mRNA expression (linear regression analysis, P=0.009), suggesting a primary role for the epigenetic events in CYGB silencing. In addition, frequent LOH was detected at the locus 17q25 in 32/48 (67%) tumours examined. It is of note that the loss of expression intensified when both LOH and hypermethylation coincided in samples (Mann–Whitney, P=0.049). These findings provide the first evidence to suggest the implication of CYGB in the pathogenesis of NSCLCs.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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