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Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes
Author(s) -
Shui Irene M.,
Wong ChaoJen,
Zhao Shanshan,
Kolb Suzanne,
Ebot Ericka M.,
Geybels Milan S.,
Rubicz Rohina,
Wright Jonathan L.,
Lin Daniel W.,
Klotzle Brandy,
Bibikova Marina,
Fan JianBing,
Ostrander Elaine A.,
Feng Ziding,
Stanford Janet L.
Publication year - 2016
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.30045
Subject(s) - dna methylation , prostate cancer , methylation , medicine , differentially methylated regions , epigenetics , oncology , odds ratio , cancer , cancer research , biology , gene expression , genetics , gene
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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 .