title: Frequent genetic and epigenetic abnormalities contribute to the deregulation of cytoglobin in non-small cell lung cancer.
abstract: 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.
authors.affiliation: University of Liverpool Cancer Research Center, Roy Castle Lung Cancer Research Programme, Liverpool, UK.
authors.forename: George
authors.initials: G
authors.lastname: Xinarianos
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McRonald
authors.forename: Janet M
authors.initials: JM
authors.lastname: Risk
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Bowers
authors.forename: Georgios
authors.initials: G
authors.lastname: Nikolaidis
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D000078842:Cytoglobin; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency / Q000235:genetics; D005914:Globins / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000627265:CYGB protein, human; D000078842:Cytoglobin; D012333:RNA, Messenger; D005914:Globins