Carcinogen exposure differentially modulates RAR-beta promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis.

The retinoic acid receptor beta (RAR-beta) gene encodes one of the primary receptors for retinoic acid, an important signaling molecule in lung growth, differentiation and carcinogenesis. RAR-beta has been shown to be down-regulated by methylation in human lung cancer. We have used previously lung tumors induced in mice to evaluate the timing and effect of specific carcinogen exposures on targeting genes altered in human lung cancer.

Aberrant promoter methylation of the transcription factor genes PAX5 alpha and beta in human cancers.

Aberrant methylation of 5'CpG islands is a key epigenetic event in many human cancers. A PCR-based technique of methylated CpG island amplification followed by representational difference analysis was used to identify genes methylated in cancer. Two of the CpG islands identified mapped to the 5' untranslated region of the PAX5 alpha and beta genes.

Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers.

Recent studies from our laboratory suggest that gene-specific methylation changes in sputum could be good intermediate markers for the early detection of lung cancer and defining the efficacy of chemopreventive interventions. The purpose of our study was to determine the prevalence for aberrant promoter methylation of the p16, O(6)-methylguanine-DNA methyltransferase (MGMT), death-associated protein (DAP) kinase, and Ras effector homologue (RASSFIA) genes in nonmalignant bronchial epithelial cells from current and former smokers in a hospital-based, case control study of lung cancer. The relationship between loss of heterozygosity, at 9p and p16 methylation in bronchial epithelium and the prevalence for methylation of these four genes in sputum from cancer-free, current and former smokers were also determined.

Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens.

Recent studies by our laboratory indicate that the p16(INK4a) gene is frequently methylated in lung tumors induced by genotoxic carcinogens and that the frequency for methylation of the estrogen receptor alpha (ER) gene varies as a function of carcinogenic exposure. The purpose of the current investigation was to define the role of these two genes in lung tumors induced by the particulate carcinogens carbon black (CB), diesel exhaust (DE) or beryllium metal. Methylation of p16 was observed in 59 and 46% of DE and CB tumors, respectively.