CpG Site–Specific Hypermethylation of <i>p16INK4α</i> in Peripheral Blood Lymphocytes of PAH-Exposed Workers

Yang, Ping; Ma, Jie; Zhang, Bo; Duan, Huawei; He, Zhini; Zeng, Junling; Zeng, Xiao‐Wen; Li, Daochuan; Wang, Qing; Xiao, Yongmei; Liu, Caixia; Qin, Xiao; Chen, Liping; Zhu, Xiaonian; Xing, Xiumei; Li, Zhifang; Zhang, Shixin; Zhang, Zhengbao; Ma, Lu; Wang, Erman; Zhuang, Zhixiong; Zheng, Yuxin; Chen, Wen

doi:10.1158/1055-9965.epi-11-0784

Cited by 61 publications

(44 citation statements)

References 54 publications

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“…Promoter hypermethylation and reduced expression of the IFN γ gene (another gene commonly down-regulated in various cancers) was observed in Jurkat cells and two human adenocarcinoma cell lines exposed to low, non-cytotoxic doses (0.1 and 1 nM) of B a P, as well as in cord white blood cells of women who were exposed to PAHs during pregnancy [50]. Hypermethylation of CpG islands within the p16 INK4α tumor suppressor gene, as well as down-regulation of expression of the gene, was observed in human bronchial epithelial cells exposed to B a P [51]. The same trend was observed in the peripheral blood of PAH-exposed workers, relative to that of non-exposed control subjects, and the degree of methylation was associated with the internal exposure and the level of DNA damage).…”

Section: Epigenetic Effects Associated With Carcinogenic Chemicalsmentioning

confidence: 99%

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

Chappell

Pogribny

Guyton

et al. 2016

Mutation Research/Reviews in Mutation Research

141

105

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Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments.

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Section: Epigenetic Effects Associated With Carcinogenic Chemicalsmentioning

confidence: 99%

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

Chappell

Pogribny

Guyton

et al. 2016

Mutation Research/Reviews in Mutation Research

141

105

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“…Dietary insufficiency of folate and other 1-carbon metabolism-dependent micronutrients, or germline or somatic mutations in members of the pathway can induce hypomethylation in tumor, and normal tissues including blood (4,14,25,26). Exogenous exposures, such as carcinogen exposure may influence methylation by inducing DNA damage or by affecting DNMT enzyme activity (4,11,27,28). Furthermore, the efficiency of DNA methylation may be affected by age (12,29).…”

Section: Causes and Consequences Of Genome-wide Hypomethylationmentioning

confidence: 99%

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

Brennan

Flanagan

2012

Cancer Prevention Research

103

104

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Cancer cells display widespread genetic and epigenetic abnormalities, but the contribution to disease risk, particularly in normal tissue before disease, is not yet established. Genome-wide hypomethylation occurs frequently in tumors and may facilitate chromosome instability, aberrant transcription and transposable elements reactivation. Several epidemiologic case-control studies have reported genomic hypomethylation in peripheral blood of cancer patients, suggesting a systemic effect of hypomethylation on disease predisposition, which may be exploited for biomarker development. However, more recent studies have failed to reproduce this. Here, we report a meta-analysis, indicating a consistent inverse association between genomic 5-methylcytosine levels and cancer risk [95% confidence interval (CI), 1.2-6.1], but no overall risk association for studies using surrogates for genomic methylation, including methylation at the LINE-1 repetitive element (95% CI, 0.8-1.7). However, studies have been highly heterogeneous in terms of experimental design, assay type, and analytical methods. We discuss the limitations of the current approaches, including the low interindividual variability of surrogate assays such as LINE1 and the importance of using prospective studies to investigate DNA methylation in disease risk. Insights into genomic location of hypomethylation, from recent whole genome, highresolution methylome maps, will help address this interesting and clinically important question. Cancer Prev Res; 5(12); 1345-57. Ó2012 AACR.

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“…Methylation of different CpG sites may affect the binding of different transcription factors that mediate specific molecular pathways in the pathogenesis of HCC, and may also be influenced by these transcription factors. Recent studies have shown that INK4A DNA hyper-methylation is associated with environmental carcinogens [47–50]. Levels and patterns of CpG methylation of INK4A DNA may therefore serve as a marker of both exposure and effect of HCC carcinogens.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of INK4A promoter methylation using pyrosequencing and circulating cell-free DNA from patients with hepatocellular carcinoma

Huang

Krocker

Kirk

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background Hyper-methylation of CpG dinucleotides in the promoter region of inhibitor of cyclin-dependent kinase 4A (INK4A) has been reported in 60%–80% of hepatocellular carcinoma (HCC). As INK4A promoter hypermethylation event occurs early in HCC progression, the quantification of INK4A promoter methylation in blood sample may represent a useful biomarker for non-invasive diagnosis and prediction of response to therapy. Methods We examined INK4A promoter methylation using circulating cell-free DNA (ccfDNA) in a total of 109 serum specimens, including 66 HCC and 43 benign chronic liver diseases. Methylation of the individual seven CpG sites was examined using pyrosequencing. Results Our results showed that there were significantly higher levels of methylated INK4A in HCC specimens than controls and that the seven CpG sites had different levels of methylation and might exist in different PCR amplicons. The area under receiver operating characteristic (ROC) curve was 0.82, with 65.3% sensitivity and 87.2% specificity at 5% (LOD), 39.0% sensitivity and 96.5% specificity at 7% LOD, and 20.3% sensitivity and 98.8% specificity at 10% LOD, respectively. Conclusions Our results support additional studies incorporating INK4A methylation testing of ccfDNA to further validate the diagnostic, predictive, and prognostic characteristics of this biomarker in HCC patients. The knowledge of the existence of epi-alleles should help improve assay design to maximize detection.

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CpG Site–Specific Hypermethylation of p16INK4α in Peripheral Blood Lymphocytes of PAH-Exposed Workers

Cited by 61 publications

References 54 publications

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

Evaluation of INK4A promoter methylation using pyrosequencing and circulating cell-free DNA from patients with hepatocellular carcinoma

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