title: Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer.
abstract: BACKGROUND
  Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer.
  
  
  METHODS
  In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1055 cases/1101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
  
  
  RESULTS
  When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.26, 95%CI=1.06-4.79), HIN1 (OR=2.14, 95%CI=1.34-3.42) and RARβ (OR=1.80, 95%CI=1.16-2.78) and decreased ORs for BRCA1 (OR=0.44, 95%CI=0.30-0.66). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST1 methylation (OR=2.79, 95%CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 (OR=0.59, 95%CI=0.41-0.86).
  
  
  CONCLUSIONS
  PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the associations between PAHs and breast cancer incidence.
authors.affiliation: Department of Epidemiology University of North Carolina, Chapel Hill, NC, USA. Electronic address: whitea@unc.edu.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: White
authors.affiliation: Departments of Preventive Medicine, New York, NY, USA; Departments of Oncological Science, New York, NY, USA; Departments of Pediatrics, Ichan School of Medicine at Mt. Sinai, New York, NY, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Preventive Medicine, New York, NY, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.affiliation: Department of Epidemiology University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McCullough
authors.affiliation: Departments of Preventive Medicine, New York, NY, USA; Departments of Biometrics, Roche Product Development in Asia-Pacific, Shanghai, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Hee Cho
authors.affiliation: Department of Epidemiology University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Conway
authors.affiliation: Department of Consulting in the Public Interest (CIPI), Lambertville, NJ, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Beyea
authors.affiliation: Departments of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Stellman
authors.affiliation: Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Steck
authors.affiliation: Department of Epidemiology University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Mordukhovich
authors.affiliation: Departments of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: Sybil M
authors.initials: SM
authors.lastname: Eng
authors.affiliation: Departments of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Beth Terry
authors.affiliation: Department of Epidemiology University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Engel
authors.affiliation: Departments of Division of Cancer Epidemiology and Genetics, Radiation Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Hatch
authors.affiliation: Departments of Epidemiology, Columbia University, New York, NY, USA; Departments of Medicine, Columbia University, New York, NY, USA.
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Neugut
authors.affiliation: Departments of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Hanina
authors.initials: H
authors.lastname: Hibshoosh
authors.affiliation: Departments of Environmental Health Sciences; Columbia University, New York, NY, USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
authors.affiliation: Department of Epidemiology University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000187:drug effects*; D004781:Environmental Exposure / Q000032:analysis*; D004785:Environmental Pollutants / Q000633:toxicity*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D055815:Young Adult
chemical_list: D004785:Environmental Pollutants; D011084:Polycyclic Aromatic Hydrocarbons
keywords: Air pollution; Environmental tobacco smoke; Grilled meat.; Methylation; Smoking