Prostate cancer is a major cause of disease and mortality among men, and each year 1.6 million men are diagnosed with and 366,000 men die of prostate cancer. In this review, we discuss the state of evidence for specific genetic, lifestyle, and dietary factors associated with prostate cancer risk. Given the biological heterogeneity of this cancer, we focus on risk factors for advanced or fatal prostate cancer. First, we provide descriptive epidemiology statistics and patterns for prostate cancer incidence and mortality around the world. This includes discussion of the impact of prostate-specific antigen screening on prostate cancer epidemiology. Next, we summarize evidence for selected risk factors for which there is strong or probable evidence of an association: genetics, obesity and weight change, physical activity, smoking, lycopene and tomatoes, fish, vitamin D and calcium, and statins. Finally, we highlight future directions for prostate cancer epidemiology research.

Background: PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort.

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.

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.