title: Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes.
abstract: DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality.
  
  
  
  A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes.
  
  
  
  Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles.
  
  
  
  This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. Cancer 2016;122:2168-77. © 2016 American Cancer Society.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Shui
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Chao-Jen
authors.initials: CJ
authors.lastname: Wong
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kolb
authors.affiliation: Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Ericka M
authors.initials: EM
authors.lastname: Ebot
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Milan S
authors.initials: MS
authors.lastname: Geybels
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Rohina
authors.initials: R
authors.lastname: Rubicz
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Wright
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: Illumina, Inc, San Diego, California.
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.affiliation: Illumina, Inc, San Diego, California.
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.affiliation: AnchorDx Corp, Guangzhou, Guangdong, China.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
mesh_terms: D000328:Adult; D000368:Aged; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D016017:Odds Ratio; D063868:Patient Outcome Assessment; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality* / Q000601:surgery; D012907:Smoking / Q000009:adverse effects
keywords: DNA methylation; epigenetics; prostate cancer; prostate cancer outcomes; smoking