Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers.
An important method for silencing tumor suppressor genes in cancers is by aberrant methylation (referred to as methylation) of CpG islands in gene promoter regions. In lung cancer, methylation of the genes retinoic acid receptor beta-2 (RARbeta-2), CDH13 (H-cadherin), p16(INK4a) (p16), RASSF1A (RAS association domain family I) is frequent. Thus, we investigated methylation of these genes in 4 different types of specimens (oropharyngeal brushes, sputum samples, bronchial brushes and bronchioloalveolar lavage [BAL] samples) of the upper aerodigestive tract epithelium from heavy smokers without evidence of cancer but with morphometric evidence of sputum atypia and compared the frequencies of methylation in the different types of specimens. In addition, we also analyzed sputum samples from 30 never smokers for methylation of these genes. Our major findings are: (i) At least one gene was methylated in one or more specimens from 48% of the smokers. However, methylation was statistically significant less frequently in never smokers compared to smokers. (ii) In general, methylation occurred more frequently in samples from the central airways (sputum, bronchial brushes) compared to the peripheral airways (BAL) and only occasionally in the oropharynx. (iii) RARbeta-2 was the most frequently methylated gene, whereas the frequency of methylation for the other genes was lower. (iv) Data from sputum samples and bronchial brushes were comparable. Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens.
Zöchbauer-Müller
Sabine
S
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA. sabine.zoechbauer@akh-wien.ac.at
Lam
Stephen
S
Toyooka
Shinichi
S
Virmani
Arvind K
AK
Toyooka
Kiyomi O
KO
Seidl
Sonja
S
Minna
John D
JD
Gazdar
Adi F
AF
D000328:Adult; D000368:Aged; D018893:Bronchoalveolar Lavage; D015820:Cadherins / Q000235:genetics; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011230:Precancerous Conditions / Q000175:diagnosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D020545:Respiratory Mucosa; D012907:Smoking / Q000009:adverse effects*; D025521:Tumor Suppressor Proteins
D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; C099972:H-cadherin; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta