title: DNA methylation modifies the association between obesity and survival after breast cancer diagnosis.
abstract: Mechanisms underlying the poor breast cancer prognosis among obese women are unresolved. DNA methylation levels are linked to obesity and to breast cancer survival. We hypothesized that obesity may work in conjunction with the epigenome to alter prognosis. Using a population-based sample of women diagnosed with first primary breast cancer, we examined modification of the obesity-mortality association by DNA methylation. In-person interviews were conducted approximately 3 months after diagnosis. Weight and height were assessed [to estimate body mass index (BMI)], and blood samples collected. Promoter methylation of 13 breast cancer-related genes was assessed in archived tumor by methylation-specific PCR and Methyl Light. Global methylation in white blood cell DNA was assessed by analysis of long interspersed elements-1 (LINE-1) and with the luminometric methylation assay (LUMA). Vital status among 1308 patients (with any methylation biomarker and complete BMI assessment) was determined after approximately 15 years of follow-up (N = 194/441 deaths due to breast cancer-specific/all-cause mortality). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) using two-sided p values of 0.05. Breast cancer-specific mortality was higher among obese (BMI ≥ 30) patients with promoter methylation in APC (HR = 2.47; 95 % CI = 1.43-4.27) and TWIST1 (HR = 4.25; 95 % CI = 1.43-12.70) in breast cancer tissue. Estimates were similar, but less pronounced, for all-cause mortality. Increased all-cause (HR = 1.81; 95 % CI = 1.19-2.74) and breast cancer-specific (HR = 2.61; 95 % CI = 1.45-4.69) mortality was observed among obese patients with the lowest LUMA levels. The poor breast cancer prognosis associated with obesity may depend on methylation profiles, which warrants further investigation.
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. lauren.mccullough@emory.edu.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McCullough
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.|Department Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.|Department Oncological Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, USA.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Division of Epidemiology, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Nikhil K
authors.initials: NK
authors.lastname: Khankari
authors.affiliation: School of Public Health Division of Epidemiology, University of California Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bradshaw
authors.affiliation: Epidemiology Branch National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: White
authors.affiliation: Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Garbowski
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, 10032, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, 10032, USA.|Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Neugut
authors.affiliation: Department of Pathology, Columbia University, New York, NY, 10032, USA.
authors.forename: Hanina
authors.initials: H
authors.lastname: Hibshoosh
authors.affiliation: Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D016019:Survival Analysis; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1
keywords: Body mass index; Breast cancer; Epigenetics; Methylation; Survival