Vigorous Physical Activity Is Associated with Lower Risk of Metastatic-Lethal Progression in Prostate Cancer and Hypomethylation in the CRACR2A Gene

Background: There is preliminary evidence linking physical activity to better prostate cancer outcomes, though the molecular mechanisms underlying this association are not clear. Methods: In a Seattle-based cohort of patients diagnosed with clinically localized prostate cancer and prospective follow-up for outcomes (n = 1,354), we studied the association between self-reported vigorous physical activity and prostate cancer progression to a metastatic-lethal phenotype. A subset of patients had prostate cancer tissue samples available for investigating DNA methylation (Infinium Human Methylation 450 BeadChip array) and exercise (n = 524). Results: Patients who had vigorous physical activity at least once per week during the year before diagnosis (similar to 79% of the cohort) were significantly less likely to progress to metastaticlethal prostate cancer compared with those who had vigorous physical activity less frequently (adjusted hazard ratio = 0.63; P = 0.029). Among the subset of men who had radical prostatectomy as primary treatment and tumor tissue available, a differentially methylated region (DMR) was identified (family-wise error rate = 0.03, hypomethylated in the weekly exercise group), with 9 methylation probes located in the promoter region of CRACR2A. This gene encodes a calcium binding protein involved in innate immune response. The methylation level of the nine CpGs was inversely correlated with CRACR2A gene expression (average correlation coefficient = -0.35). Conclusions: Vigorous physical activity before diagnosis is associated with epigenetic alterations of CRACR2A and prostate cancer metastatic-lethal progression. Impact: This analysis provides strong evidence for the association between vigorous physical activity and a less likelihood to develop metastatic-lethal progression, and a suggestive link between exercise and DNA methylation in the CRACRA2A gene.