title: Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study.
abstract: OBJECTIVE
  Tobacco smoking is a risk factor in several cancers, yet its roles as a putative etiologic exposure or poor prognostic factor in breast cancer are less clear. Altered DNA methylation contributes to breast cancer development and may provide a mechanistic link between smoking and gene expression changes leading to cancer development or progression.
  
  
  METHODS
  Using a cancer-focused array, we examined methylation at 933 CpGs in 517 invasive breast tumors in the Carolina Breast Cancer Study to determine whether methylation patterns differ by exposure to tobacco smoke. Multivariable generalized linear regression models were used to compare tumor methylation profiles between smokers and never smokers, overall, or stratified on hormone receptor (HR) status.
  
  
  RESULTS
  Modest differences in CpG methylation were detected at p < 0.05 in breast tumors from current or ever smokers compared with never smokers. In stratified analyses, HR- tumors from smokers exhibited primarily hypomethylation compared with tumors from never smokers; hypomethylation was similarly detected within the more homogeneous basal-like subtype. Most current smoking-associated CpG loci exhibited methylation levels in former smokers that were intermediate between those in current and never smokers and exhibited progressive changes in methylation with increasing duration of smoking. Among former smokers, restoration of methylation toward baseline (never smoking) levels was observed with increasing time since quitting. Moreover, smoking-related hypermethylation was stronger in HR+ breast tumors from blacks than in whites.
  
  
  CONCLUSIONS
  Our results suggest that breast tumor methylation patterns differ with tobacco smoke exposure; however, additional studies are needed to confirm these findings.
authors.affiliation: Department of Epidemiology, School of Public Health, University of North Carolina, Campus Box 7435, Chapel Hill, NC, 27599, USA. kconway@med.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA. kconway@med.unc.edu.
authors.forename: Kathleen
authors.identifier: http://orcid.org/0000-0002-5540-3347
authors.initials: K
authors.lastname: Conway
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Edmiston
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Eloise
authors.initials: E
authors.lastname: Parrish
authors.affiliation: Department of Biostatistics, School of Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bryant
authors.affiliation: Department of Epidemiology, School of Public Health, University of North Carolina, Campus Box 7435, Chapel Hill, NC, 27599, USA.
authors.forename: Chiu-Kit
authors.initials: CK
authors.lastname: Tse
authors.affiliation: School of Nursing, Virginia Commonwealth University, Richmond, VA, 23298, USA.|Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Swift-Scanlan
authors.affiliation: Department of Epidemiology, School of Public Health, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McCullough
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, 11794-3600, USA.
authors.forename: Pei Fen
authors.initials: PF
authors.lastname: Kuan
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012907:Smoking / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm
keywords: Breast cancer; Breast tumor; Epigenetic; Methylation; Smoking