title: Expression of the p16(INK4a) gene product, methylation of the p16(INK4a) promoter region and expression of the polycomb-group gene BMI-1 in squamous cell lung carcinoma and premalignant endobronchial lesions.
abstract: It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear.
authors.affiliation: Department of Pathology, Vrije Universiteit, University Medical Center, Amsterdam, The Netherlands.
authors.forename: R H J
authors.initials: RH
authors.lastname: Breuer
authors.forename: P J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: G T
authors.initials: GT
authors.lastname: Sutedja
authors.forename: R G A B
authors.initials: RG
authors.lastname: Sewalt
authors.forename: A P
authors.initials: AP
authors.lastname: Otte
authors.forename: P E
authors.initials: PE
authors.lastname: Postmus
authors.forename: C J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: F M
authors.initials: FM
authors.lastname: Raaphorst
authors.forename: E F
authors.initials: EF
authors.lastname: Smit
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000503:physiopathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology*; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis*; D063150:Polycomb Repressive Complex 1; D011230:Precancerous Conditions / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000096:biosynthesis*
chemical_list: C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1