title: Aberrant DNA methylation of some tumor suppressor genes in lung cancers from workers with chromate exposure.
abstract: Our previous studies revealed a variety of genetic changes in lung cancers from chromate-exposed workers (chromate lung cancer). In the present study, we examined epigenetic changes in chromate lung cancers. Nested-methylation-specific PCR was employed in studying the methylation of CpG islands in the APC, MGMT, hMLH1 genes in 36 chromate lung cancers and 25 nonchromate lung cancers. Methylation in chromate lung cancers was detected at 86% for APC, 20% for MGMT, and 28% for hMLH1. Whereas, it occurred at lower frequencies in nonchromate lung cancers, particularly in APC (44%) and hMLH1 (0%) genes. Our previous study showed that methylation of p16 gene in chromate lung cancer and nonchromate lung cancer was 33% and 26%, respectively. The mean methylation index (MI), a reflection of the overall methylation status, was significantly higher in chromate lung cancers than nonchromate lung cancers (0.41 vs. 0.21, P=0.001). Methylation of multiple genes (particularly hMLH1, p16, and APC genes) had experienced more than 15 yr of chromate exposure in chromate lung cancer (MI: <15 yr; 0.19, ≥ 15 yr, 0.42). There is a significant correlation of p16 and hMLH1 methylation with the expressional decrease or loss of the corresponding gene products (P=0.037 and 0.024) respectively, and an inverse correlation between APC and MGMT methylation (P = 0.014). This study provides a novel evidence for the chromium carcinogenesis that chromate lung cancer is linked to the progressive methylation of some tumor suppressor genes, which may be related to genomic instability.
authors.affiliation: Department of Respiratory Medicine, Sohag Faculty of Medicine, Sohag University, Sohag, Egypt.
authors.forename: Abdellah H K
authors.initials: AH
authors.lastname: Ali
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kondo
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Namura
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Senba
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takizawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Toba
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kenzaki
authors.forename: Shoji
authors.initials: S
authors.lastname: Sakiyama
authors.forename: Akira
authors.initials: A
authors.lastname: Tangoku
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D002840:Chromates / Q000633:toxicity*; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D044127:Epigenesis, Genetic; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D009784:Occupational Diseases / Q000139:chemically induced* / Q000235:genetics*; D016273:Occupational Exposure; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002840:Chromates; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes