Alexandra J White1, Jia Chen2,3,4, Lauren E McCullough5, Xinran Xu6, Yoon Hee Cho7, Susan L Teitelbaum2, Alfred I Neugut8,9, Mary Beth Terry8, Hanina Hibshoosh10, Regina M Santella7, Marilie D Gammon5. 1. Department of Epidemiology, University of North Carolina, CB#7435, McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA. whitea@unc.edu. 2. Departments of Preventive Medicine, Ichan School of Medicine at Mt. Sinai, New York, NY, USA. 3. Departments of Oncological Science, Ichan School of Medicine at Mt. Sinai, New York, NY, USA. 4. Departments of Pediatrics, Ichan School of Medicine at Mt. Sinai, New York, NY, USA. 5. Department of Epidemiology, University of North Carolina, CB#7435, McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA. 6. Research Center for Translational Medicine, Shanghai East Hospital of Tongji University School of Medicine, Shanghai, China. 7. Department of Environmental Health Sciences, Columbia University, New York, NY, USA. 8. Department of Epidemiology, Columbia University, New York, NY, USA. 9. Department of Medicine, Columbia University, New York, NY, USA. 10. Department of Pathology, Columbia University, New York, NY, USA.
Abstract
PURPOSE: Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH-DNA adducts, methylation, and breast cancer are unknown. The objectives of this study were to (1) assess associations between PAH-DNA adducts, and breast cancer, stratified by DNA methylation markers and (2) examine interactions between adducts and DNA methylation in association with breast cancer and tumor subtype. METHODS: In a population-based case-control study, promoter methylation of 13 breast cancer-related genes was measured in tumor tissue (n = 765-851 cases). Blood DNA from breast cancer cases (n = 873) and controls (n = 941) was used to assess PAH-DNA adducts and global methylation. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI); and the ratio of the OR (ROR) was used to assess heterogeneity. RESULTS: Women with detectable PAH-DNA adducts and methylated RARβ (ROR 2.69, 95% CI 1.02-7.12; p for interaction = 0.03) or APC (ROR 1.76, 95% CI 0.87-3.58; p for interaction = 0.09) genes were more likely to have hormone receptor-positive tumors than other subtypes. Interactions with other methylation markers were not apparent (p ≥ 0.10). The association between adducts and breast cancer did not vary by methylation status of the tumor nor did adducts associate with global methylation in the controls. CONCLUSIONS: Gene-specific methylation of RARβ, and perhaps APC, may interact with PAH-DNA adducts to increase risk of hormone receptor-positive breast cancer. There was little evidence that adducts were associated with or interacted with other methylation markers of interest.
PURPOSE:Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH-DNA adducts, methylation, and breast cancer are unknown. The objectives of this study were to (1) assess associations between PAH-DNA adducts, and breast cancer, stratified by DNA methylation markers and (2) examine interactions between adducts and DNA methylation in association with breast cancer and tumor subtype. METHODS: In a population-based case-control study, promoter methylation of 13 breast cancer-related genes was measured in tumor tissue (n = 765-851 cases). Blood DNA from breast cancer cases (n = 873) and controls (n = 941) was used to assess PAH-DNA adducts and global methylation. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI); and the ratio of the OR (ROR) was used to assess heterogeneity. RESULTS:Women with detectable PAH-DNA adducts and methylated RARβ (ROR 2.69, 95% CI 1.02-7.12; p for interaction = 0.03) or APC (ROR 1.76, 95% CI 0.87-3.58; p for interaction = 0.09) genes were more likely to have hormone receptor-positive tumors than other subtypes. Interactions with other methylation markers were not apparent (p ≥ 0.10). The association between adducts and breast cancer did not vary by methylation status of the tumor nor did adducts associate with global methylation in the controls. CONCLUSIONS: Gene-specific methylation of RARβ, and perhaps APC, may interact with PAH-DNA adducts to increase risk of hormone receptor-positive breast cancer. There was little evidence that adducts were associated with or interacted with other methylation markers of interest.
Entities:
Keywords:
Breast cancer; DNA methylation; Polycyclic aromatic hydrocarbons
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