DNA Methylation: An Alternative Pathway to Cancer

Wajed, S; Laird, Peter W.; DeMeester, Tom R.

doi:10.1097/00000658-200107000-00003

Cited by 291 publications

(199 citation statements)

References 66 publications

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“…Aberrant DNA hypermethylation has been increasingly recognized as a frequent molecular alteration in cancer [1,2]. This epigenetic modification occurs at the cytosines of CpG dinucleotide-rich regions, which are mostly unmethylated in normal tissues.…”

Section: Introductionmentioning

confidence: 99%

DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study

Tao

Shields

Nie

et al. 2008

Breast Cancer Res Treat

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Aberrant DNA hypermethylation of gene promoter regions has been increasingly recognized as a common molecular alteration in carcinogenesis. We evaluated the association between major clinicopathological features and hypermethylation of genes in tumors among 803 incidence breast cancer cases from a large population-based case-control study conducted in Western New York State. DNA samples were isolated from archive paraffin embedded tumor tissue and were analyzed for hypermethylation status of the E-cadherin, p16, and RAR-β 2 genes using real time methylation-specific polymerase chain reaction. The frequencies of hypermethylation were 20.0% for E-cadherin, 25.9% for p16, and 27.5% for RAR-β 2 genes. For postmenopausal women, hypermethylation of E-cadherin tended to be more likely in progesterone receptor (PR) negative than in PR-positive tumors (odds ratio (OR), 1.41; 95% confidence interval (CI), 0.91-2.18). Hypermethylation of p16 tended to be more frequent among estrogen receptor (ER) negative cases than ER-positive cases (OR, 1.51; 95% CI, 1.01-2.32). Hypermethylation of RAR-β 2 gene was inversely associated with histological and nuclear grade of breast cancer.

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Section: Introductionmentioning

confidence: 99%

DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study

Tao

Shields

Nie

et al. 2008

Breast Cancer Res Treat

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“…Consistent with this notion, the methylation profile of individual genes seems to be different in various tumor types. Certain genes, such as 14-3-3σ, RASSF1A and P16INK4a, are commonly methylated in multiple human cancers (Wajed et al, 2001;Pulukuri and Rao, 2006), whereas others show high frequencies of methylation only in specific tumors. One example is the GSTP1 gene that is highly methylated in breast and prostate cancers but is largely unmethylated in other types of tumors (Das and Singal, 2004;Esteller et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

et al. 2007

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Gene silencing via CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. Previous studies have shown that the TIMP-2 gene, which is an endogenous inhibitor of matrix metalloproteinases involved in cell invasion and tumorigenesis, is downregulated or silenced in a variety of human cancer cell lines. Here, we investigated the mechanism underlying TIMP-2 expression in prostate cancer cell lines and primary prostate tumor samples. We observed a strong correlation between promoter hypermethylation and lost expression of TIMP-2 gene, which was supported by other results demonstrating that promoter demethylation by 5-aza-2′-deoxycytidine and trichostatin A reactivated TIMP-2 and restored its expression in TIMP-2-silenced metastatic prostate cell lines. These result were further substantiated by a chromatin immunoprecipitation assay, showing the preferential binding of MeCP2 to methylated CpG island in TIMP-2-silenced metastatic prostate cell lines. In vitro Matrigel invasion assays showed that reexpression of TIMP-2 after a combined treatment with 5-aza and TSA in metastatic prostate cells resulted in a significant reduction of tumor cell invasion. Furthermore, CpG methylation of TIMP-2 promoter was also shown in primary prostate tumors that expressed decreased TIMP-2 protein levels. These results suggest that the downregulation of the TIMP-2 gene is associated with promoter methylation and that this may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease.

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“…2 It has been proposed that DNA methylation, one of the best known epigenetic mechanisms, shares critical roles with DNA mutations in the theoretical continuum for exposure to cancer. 3,4 One potential mechanism for environmental factors is through hypermethylation or hypomethylation on somatic cells, leading to activation or silencing of key genes in critical pathways of cancer. 5,6 From some years, the disruption of DNA methylation status by exposure to genotoxic agents has been an issue in the literature, but the clear demonstration that such epigenetic alterations were caused by one or more specific agents in people has been demanding (for a review see Ref.…”

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confidence: 99%

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

Pavanello

Bollati

Pesatori

et al. 2009

Intl Journal of Cancer

139

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We investigated the effect of chronic exposure to polycyclic aromatic hydrocarbons (PAHs) on DNA methylation states (percentage of methylated cytosines (%mC)) in Polish male nonsmoking coke-oven workers and matched controls. Methylation states of gene-specific promoters (p53, p16, HIC1 and IL-6) and of Alu and LINE-1 repetitive elements, as surrogate measures of global methylation, were quantified by pyrosequencing in peripheral blood lymphocytes (PBLs). DNA methylation was evaluated in relation to PAH exposure, assessed by urinary 1-pyrenol and anti-benzo [a] We found that Alu and LINE-1 methylation levels and those of the inflammatory cytokine IL-6, to a lesser extent, were higher in polycyclic aromatic hydrocarbon (PAH)-exposed coke-oven workers than controls (p < 0.001 and p 5 0.094). Conversely, methylation of p53 and HIC1 tumor suppressors was lower in workers compared with controls (p < 0.001 and p < 0.05). Global and IL-6 hypermethylation and p53 hypomethylation were significantly correlated, not only to PAH-exposure (urinary 1-pyrenol) but also to the anti-B[a]PDE-DNA adduct levels (p < 0.01). Overall, linear multivariate regression analysis showed that the only significant determinant of increasing micronuclei (MN) (p < 0.01) was p53 hypomethylation and not the other LINE-1, Alu, p53, HIC1 and IL-6 methylation states.Gene-specific promoters (mainly p53) and global (Alu and LINE-1 repeats) DNA methylation changes in circulating peripheral blood lymphocytes (PBLs), related to anti-B[a]PDE-DNA adduct and MN, suggest that these events could be determined to identify subjects at high cancer risk.Understanding how environmental factors are involved in cancer etiology and development is one of the main goals of biomedical research. 1 Extensive research has been conducted to determine how known or potential environmental carcinogens modify the DNA sequence, as a component of malignant transformation. However, an investigative approach exclusively based on genetic damage, as well as on inheritance of genetic variants, has been revealed to be insufficient to account for multistage carcinogenic processes. 2 It has been proposed that DNA methylation, one of the best known epigenetic mechanisms, shares critical roles with DNA mutations in the theoretical continuum for exposure to cancer. 3,4 One potential mechanism for environmental factors is through hypermethylation or hypomethylation on somatic cells, leading to activation or silencing of key genes in critical pathways of cancer. 5,6 From some years, the disruption of DNA methylation status by exposure to genotoxic agents has been an issue in the literature, but the clear demonstration that such epigenetic alterations were caused by one or more specific agents in people has been demanding (for a review see Ref. 7 and references therein).Benzo [a]pyrene (B[a]P), the most well-studied PAH carcinogen (especially of the lung), has a well-established genotoxic mechanism, via metabolic activation to diol epoxide. 8 The stereoselective binding of anti-benzo[a]pyrene di...

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DNA Methylation: An Alternative Pathway to Cancer

Cited by 291 publications

References 66 publications

DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study

DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study

Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

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