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.

Quantitative detection of TUSC3 promoter methylation -a potential biomarker for prognosis in lung cancer

“…In the patients studied, MGMT methylation was less frequently observed in lung tumor tissues compared with other studies, which describe methylation frequencies of 10.0-77.8% (3,4,6,8,12,16,17). In contrast to the present study, the majority of other studies did not analyze normal tissue; therefore, statements concerning the use of MGMT methylation in the early detection of lung cancer by analyzing non-malignant samples cannot be reasonably made.…”

“…These six genes were chosen as they all appear to be relevant in tumor development and progression. The inactivation and, therefore, loss of expression of MGMT and RASSF1A in lung cancer has been described previously (3)(4)(5)(6)8,(12)(13)(14)(15)(16)(17). The reduced expression of RASAL1 was observed in several malignant tumors, including brain, head and neck, bladder, breast, colorectal, hepatocellular and thyroid carcinoma (18)(19)(20)(21), and appears to be associated with neoplastic progression (19).…”

“…In future, the knowledge of the methylation status of tumor related genes could be helpful for the identification of persons at risk, the early detection of lung cancer and for the prediction of prognosis and therapeutic success. Certain studies suspect an association between promoter methylation and smoking habits (10) or exposure to environmental and industrial factors, such as smoky coal emission or chromate exposure (6,11).…”

Epigenetics in Head and Neck Squamous Cell Carcinoma

“…Klein et al (2002) reported for the first time that potassium chromate, a carcinogen, causes aberrant DNA methylation and silences a reported gene in a mammalian cell line. Ali et al (2011) found higher rates of aberrant methylation in the promoters of three tumor-suppressor genes, APC (adenomatosis polyposis coli), MGMT (O 6 -methylguanine-DNA methyltransferase), and hMLH1 in lung cancers of chromate workers as compared to non-chromate lung cancer controls (95% versus 52%), with concordant methylation of multiple loci observed in more chromate lung cancers than in nonchromate ones (48% versus 12%). Chromate was also linked to post-translational histone modifications.…”

“…An interesting example is provided by hexavalent chromium, to which half a million workers in the United States and several million individuals worldwide are occupationally exposed (Ali et al, 2011). Until recently, chromium was thought to cause cancer only through its ability to damage DNA (Arita & Costa 2009).…”