Promoter methylation of retinoic acid receptor beta 2 and the development of second primary lung cancers in non-small-cell lung cancer.
OBJECTIVE
To investigate whether the promoter hypermethylation of retinoic acid receptor beta 2 (RARbeta2) is associated with the development of second primary lung cancers (SPLCs) differentially according to smoking status in primary non-small-cell lung cancer (NSCLC).


METHODS
We retrospectively analyzed the relationship between RARbeta2 methylation and the SPLC development in a total of 342 NSCLCs. The methylation status of RARbeta2 was determined by using methylation-specific polymerase chain reaction. The difference in the time to SPLC development was analyzed by using the log-rank test and the Cox proportional hazards model. The median follow-up was 4.1 years.


RESULTS
SPLCs developed in 19 (5.6%) of the 342 NSCLCs, and overall incidence rate of SPLC development was 1.54 per 100 patient-years. SPLCs did not occur in 39 patients who had not smoked. After controlling for possible confounding factors, the hazard of failure for former smokers with RARbeta2 hypermethylation was about 2.87 (95% CI, 0.92 to 13.64; P =.08) times higher compared to those without RARbeta2 methylation. However, for current smokers, hypermethylation of the RARbeta2 was found to have a protective effect against the SPLC development (hazard ratio = 0.23; 95% CI, 0.11 to 0.87; P =.03).


CONCLUSIONS
Hypermethylation of RARbeta2 promoter had a differential effect on the development of SPLCs in NSCLC, and this was dependent on smoking status. Our study suggests that a combination of retinoids and/or a demethylating agent may be effective in the prevention of SPLCs in never-smokers and former smokers with NSCLC.
Center for Genome Research, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jin Seuk
JS
Kim
Haengbung
H
Lee
Hojoong
H
Kim
Young Mog
YM
Shim
Joungho
J
Han
Joobae
J
Park
Duk-Hwan
DH
Kim
D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000473:pathology / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000453:epidemiology*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012189:Retrospective Studies; D012907:Smoking; D013997:Time Factors
D004273:DNA, Neoplasm; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta