Carcinogenesis Advance Access published online on May 12, 2009
Carcinogenesis, doi:10.1093/carcin/bgp114
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Concomitant Promoter Methylation of Multiple Genes in Lung Adenocarcinomas from Current, Former and Never smokers
1 Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, U.S.A
2 Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, U.S.A
3 Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, U.S.A
To whom all correspondence should be addressed. Dr. Steven Belinsky, Lung Cancer Program, 2425 Ridgecrest Dr. SE, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, E-mail: sbelinsk{at}LRRI.org, Phone: 505-348-9465, Fax: 505-348-4990
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 to 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 pair wise comparisons. A significant association was seen between 138 (42%) of the possible 325 pair-wise comparisons. Most notably, methylation of MMP2, BHLHB4, or p16 was significantly associated with methylation of 16 – 19 other genes, thus predicting for a wide-spread 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 coordinated event.
Key Words: Lung cancer • adenocarcinoma • smoking • methylation • never smokers
Received January 22, 2009; revised April 3, 2009; accepted May 2, 2009.