Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure.
Tobacco smoke causes lung cancer in smokers and in never-smokers exposed to second-hand tobacco smoke (SHS). Nonetheless, molecular mechanisms of lung cancer in SHS-exposed never-smokers are still elusive. We studied lung cancers from current smokers (n = 109), former smokers (n = 56) and never-smokers (n = 47) for promoter hypermethylation of five tumour suppressor genes--p16, RARB, RASSF1, MGMT and DAPK1--using methylation-specific polymerase chain reaction. Lung tumours from ever-smokers suggested an increased risk of p16 hypermethylation as compared to never-smokers (P = 0.073), with former smokers having the highest frequency of p16 hypermethylation (P = 0.044 versus current smokers and P = 0.009 versus never-smokers). In the never-smoking group, p16 hypermethylation was seen in lung tumours from SHS-exposed individuals (4/33; 12%) but in none of the non-exposed individuals (0/9). The overall occurrence of hypermethylation (measured both as methylation index and as number of genes affected) was similar in those ever exposed to tobacco smoke (smokers, SHS-exposed never-smokers) and differed from non-exposed never-smokers. In multivariate analysis, p16 hypermethylation was more prevalent in lung tumours from male than female patients (P = 0.018) and in squamous cell carcinomas than in adenocarcinomas (P = 0.025). Occurrence of TP53 mutation in the tumour was associated with hypermethylation of at least one gene (P = 0.027). In all, our data suggest that promoter hypermethylation pattern in SHS-exposed never-smokers resembles that observed in smokers. Association between TP53 mutation, a hallmark of smokers' lung cancer, and methylation of one or more of the lung cancer-related genes studied, provides further evidence for common tobacco smoke-related origin for both types of molecular alterations.
Faculty of Natural Sciences, Vilnius University, Ciurlionio 21, LT03101 Vilnius, Lithuania.
Asta
A
Scesnaite
Sonata
S
Jarmalaite
Pertti
P
Mutanen
Sisko
S
Anttila
Fredrik
F
Nyberg
Simone
S
Benhamou
Paolo
P
Boffetta
Kirsti
K
Husgafvel-Pursiainen
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D064550:Death-Associated Protein Kinases; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014026:Nicotiana
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D014028:Tobacco Smoke Pollution; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045643:DNA Repair Enzymes