Carcinogenesis Advance Access originally published online on May 12, 2009
Carcinogenesis 2009 30(7):1132-1138; doi:10.1093/carcin/bgp114
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Concomitant promoter methylation of multiple genes in lung adenocarcinomas from current, former and never smokers
Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108, USA
1 Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
2 Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
* To whom correspondence should be addressed. Tel: +1 505 348 9465; Fax: +1 505 348 4990; Email: sbelinsk{at}lrri.org
Aberrant promoter hypermethylation is one of the major mechanisms in carcinogenesis and some critical growth regulatory genes have shown commonality in methylation across solid tumors. Twenty-six genes, 14 identified through methylation in colon and breast cancers, were evaluated using primary lung adenocarcinomas (n = 175) from current, former and never smokers. Tumor specificity of methylation was validated through comparison of 14 lung cancer cell lines to normal human bronchial epithelial cells derived from bronchoscopy of 20 cancer-free smokers. Twenty-five genes were methylated in 11–81% of primary tumors. Prevalence for methylation of TNFRSF10C, BHLHB5 and BOLL was significantly higher in adenocarcinomas from never smokers than smokers. The relation between methylation of individual genes was examined using pairwise comparisons. A significant association was seen between 138 (42%) of the possible 325 pairwise comparisons. Most notably, methylation of MMP2, BHLHB4 or p16 was significantly associated with methylation of 16–19 other genes, thus predicting for a widespread methylation phenotype. Kaplan–Meier log-rank test and proportional hazard models identified a significant association between methylation of SULF2 (a pro-growth, -angiogenesis and -migration gene) and better patient survival (hazard ratio = 0.23). These results demonstrate a high degree of commonality for targeted silencing of genes between lung and other solid tumors and suggest that promoter hypermethylation in cancer is a highly co-ordinated event.
Abbreviations: DAC, 5-aza-deoxycytidine; NHBEC, normal human bronchial epithelial cells; PCR, polymerase chain reaction; RT–PCR, reverse transcription–polymerase chain reaction; TSA, trichostatin A
Received January 22, 2009; revised April 3, 2009; accepted May 2, 2009.