Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes

Abstract

Background DNA methylation has been hypothesized as a mechanism to explain the association between smoking and adverse prostate cancer (PCa) outcomes. We aimed to assess whether smoking was 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 primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes and tumor tissue profiled for DNA methylation. Ninety percent of men also had matched tumor gene expression data. We conducted a methylome-wide analysis to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, we evaluated their correlation with mRNA expression of corresponding genes. 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 ten of these were strongly correlated with mRNA expression (AOX1, CLDN5, EBF1, HOXA7, LGALS3, MAPT, PCDHGA/PCDHGB, PON3, SYCP2L, and ZSCAN12). Men who were in the highest tertile of the smoking-methylation score derived from these DMRs had a higher risk of recurrence (OR: 2.29; 95% CI: 1.42-3.72) and lethal disease (OR: 4.21; 95% CI: 1.65-11.78) compared to men in the lower two tertiles. Conclusions This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain, at least a portion 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.

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