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DNA methylation: a marker for carcinogen exposure and cancer risk.

ABSTRACT: Cancers arise as a consequence of multiple genetic and epigenetic alterations. Many genes aberrantly methylated in cancers have been identified in recent years, and their use in cancer diagnosis and therapy is currently under investigation. During our genome-wide screening for a novel tumor-suppressor gene in gastric cancers, we found that only a small amount of aberrant methylation was present, even in non-cancerous gastric mucosae. A subsequent large-scale analysis of the gastric mucosae of healthy individuals and gastric cancer patients using quantitative methylation-specific PCR (qMSP) revealed that Helicobacter pylori infection potently induced aberrant DNA methylation in non-cancerous gastric mucosae and that these high methylation levels can decrease following cessation of the H. pylori infection. Helicobacter pylori infection induced the methylation of specific genes among 48 genes that can be methylated in gastric cancer cell lines. Most importantly, the methylation levels in the gastric mucosae of individuals without H. pylori infection correlated with their risk of gastric cancer. These findings show that a field for cancerization is formed by H. pylori infection and that this field can be measured using DNA methylation as a marker. The concept of an "epigenetic field for cancerization" has been also demonstrated for colon and breast cancers, and it is possibly present for other cancers and other diseases. Applied knowledge of epigenetic changes in human diseases has now started to make an impact on the prevention, diagnostics, and therapeutics of these diseases.

SUBMITTER: Nakajima T

PROVIDER: S-EPMC2698244 | biostudies-other | 2008 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundPrevious studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment.ObjectivesA complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes.MethodsMale neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 ?g?BPA/kg?BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS).ResultsThe lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 ?g/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses.ConclusionsDevelopmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050.

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DNA methylation: a marker for carcinogen exposure and cancer risk.

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