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Vigorous Physical Activity Is Associated with Lower Risk of Metastatic–Lethal Progression in Prostate Cancer and Hypomethylati

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Vigorous Physical Activity Is Associated with Lower Risk of Metastatic–Lethal Progression in Prostate Cancer and Hypomethylati Published OnlineFirst November 21, 2018; DOI: 10.1158/1055-9965.EPI-18-0622 Research Article Cancer Epidemiology, Biomarkers Vigorous Physical Activity Is Associated with & Prevention Lower Risk of Metastatic–Lethal Progression in Prostate Cancer and Hypomethylation in the CRACR2A Gene James Y. Dai1,2, Bo Wang3, Xiaoyu Wang1, Anqi Cheng2, Suzanne Kolb1, Janet L. Stanford1,4, and Jonathan L. Wright1,5 Abstract Background: There is preliminary evidence linking physical prostatectomy as primary treatment and tumor tissue avail- activity to better prostate cancer outcomes, though the molec- able, a differentially methylated region (DMR) was identified ular mechanisms underlying this association are not clear. (family-wise error rate ¼ 0.03, hypomethylated in the weekly Methods: In a Seattle-based cohort of patients diagnosed exercise group), with 9 methylation probes located in the with clinically localized prostate cancer and prospective fol- promoter region of CRACR2A. This gene encodes a calcium low-up for outcomes (n ¼ 1,354), we studied the association binding protein involved in innate immune response. The between self-reported vigorous physical activity and prostate methylation level of the nine CpGs was inversely correlated cancer progression to a metastatic–lethal phenotype. A subset with CRACR2A gene expression (average correlation coeffi- of patients had prostate cancer tissue samples available for cient ¼ –0.35). investigating DNA methylation (Infinium HumanMethyla- Conclusions: Vigorous physical activity before diagnosis is tion450 BeadChip array) and exercise (n ¼ 524). associated with epigenetic alterations of CRACR2A and pros- Results: Patients who had vigorous physical activity at least tate cancer metastatic–lethal progression. once per week during the year before diagnosis (79% of the Impact: This analysis provides strong evidence for the cohort) were significantly less likely to progress to metastatic– association between vigorous physical activity and a less lethal prostate cancer compared with those who had vigorous likelihood to develop metastatic–lethal progression, and a physical activity less frequently (adjusted hazard ratio ¼ 0.63; suggestive link between exercise and DNA methylation in the P ¼ 0.029). Among the subset of men who had radical CRACRA2A gene. Introduction ical activity with better outcomes (3–5), including a reduction in cancer progression (3), prostate cancer–specific mortality (4, 5), Prostate cancer is the most frequently diagnosed cancer among and all-cause mortality (4, 5); however, the molecular pathways men in the United States (1, 2). There are also close to 3 million underlying these associations remain unclear. The hypothesized prostate cancer survivors in the United States, yet over 27,000 men mechanisms include physical activity inducing alterations in die each year from the disease (1, 2). More than 80% of patients circulating factors such as insulin-like grow factor I (IGF1), with prostate cancer are diagnosed with localized disease with inflammatory cytokines and tumor vascularization that may excellent long-term survival. However, a subset of men with inhibit proliferation and promote apoptosis of prostate cancer localized prostate cancer will progress to develop metastasis and cells (6–9). cancer-specific mortality. Among men diagnosed with clinically Numerous studies have been conducted to investigate exercise- localized prostate cancer, there is growing evidence linking phys- induced molecular alterations, including DNA methylation in blood and some cancer tissues (10). Although observational studies have reported weak correlations between physical activity 1Division of Public Health Sciences, Fred Hutchison Cancer Research Center, 2 and DNA methylation, interventional studies have consistently Seattle, Washington. Department of Biostatistics, University of Washington fi fi School of Public Health, Seattle, Washington. 3Department of Laboratory identi ed a signi cant impact of exercise on DNA methylation of Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University a number of genes involved in metabolism, muscle growth and School of Medicine, Shanghai, China. 4Department of Epidemiology, University inflammation across different tissues (muscle, adipose, blood). of Washington School of Public Health, Seattle, Washington. 5Department of This impact may depend on the genetic pathways involved, tissue- Urology, University of Washington School of Medicine, Seattle, Washington. specificity, and intensity of exercise. The DNA methylation Corresponding Authors: James Y. Dai, Fred Hutchinson Cancer Research changes associated with exercise have not always correlated with Center, 1100 Fairview Avenue North, M2-C200, Seattle, WA 98109. Phone: changes in gene expression (10). For prostate cancer, it has been 206-667-6364; Fax: 206-667-4812; E-mail: [email protected]; and Janet L. observed that regular exercise improves patient outcomes. It is Stanford, [email protected] therefore of interest to investigate alterations of DNA methylation doi: 10.1158/1055-9965.EPI-18-0622 induced by exercise and explore potential beneficial effects of Ó2018 American Association for Cancer Research. exercise that may be mediated by DNA methylation. One study 258 Cancer Epidemiol Biomarkers Prev; 28(2) February 2019 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst November 21, 2018; DOI: 10.1158/1055-9965.EPI-18-0622 Physical Activity, DNA Methylation, and Prostate Cancer reported that transcripts of cell-cycle and DNA repair genes may be prostatectomy specimens were used to make hematoxylin and modulated in normal prostate tissue by vigorous activity (11). eosin slides, which were reviewed by a prostate pathologist to However, we are not aware of any studies that have focused on confirm the presence and location of prostate cancer. Areas con- exercise and DNA methylation in primary prostate cancer tissues. taining 75% tumor tissue were marked and two 1-mm cores We hypothesize that physical activity alters DNA methylation were taken from the dominant cancer focus for DNA (using profiles in prostate tumor tissue, and these changes may be RecoverAll Total Nucleic Acid Isolation Kit—Applied Biosciences) molecular intermediaries that lead to better prostate cancer out- and RNA (RNeasy FFPE Kit—Qiagen Inc.) purification. comes. To test this hypothesis, we conducted a methylome-wide Tumor DNA samples were bisulfite converted using the EZ analysis in a cohort of men with localized prostate cancer for DNA methylation kit (Zymo Research). The Infinium Human whom self-reported vigorous physical activity data before diag- Methylation450 BeadChip (Illumina) measured genome-wide nosis and long-term follow-up data for metastatic lethal progres- CpG methylation using beads with target-specific probes designed sion were both available. The study aimed to investigate the to interrogate >485,000 CpG sites (14). The correlations between relationship between vigorous physical activity and prostate blind duplicates ranged from 0.96 to 0.99, and were >0.99 for cancer metastatic lethal progression, to identify differentially replicates across plates. Subset-quantile within array normaliza- methylated positions (DMP) and differentially methylated tion (SWAN; ref. 15) and batch adjustment through ComBat (16) regions (DMR) in prostate tumor tissue that are associated with were completed. After processing, methylation profiles on vigorous physical activity, and to assess whether the changes in 478,998 CpG sites were available for 523 men. The DNA meth- methylation, if any, were associated with corresponding changes ylation b-value ranges from 0 (unmethylated) to 1 (fully meth- in mRNA expression and metastatic lethal progression. ylated) as an estimate of the percentage of DNA in the tissue sample that is methylated at each CpG probe. Materials and Methods Matched tumor gene expression data for >29,000 transcripts Study population were available for 469 (90%) men with methylation data. The Participants of two previously described population-based Whole-Genome cDNA-mediated Annealing, Selection, extension studies of men with histologically confirmed, clinically localized and Ligation (DASL) HT Assay (Illumina) developed specifically prostate cancer (n ¼ 1,354) were included in the analysis (12–13). for use with archival FFPE specimens was used (17). Data were Men from the first study were diagnosed at ages 40 to 64 years quantile normalized, log2 transformed and batch effects were during 1993–1996 and men from the second study were diag- removed using ComBat (16). The procedures for quality control nosed at ages 35 to 74 years during 2002–2005. Information on and data processing have been described elsewhere (18). demographics, medical history and environmental/lifestyle expo- Statistical methods sures up to and including the date of diagnosis was collected by in- Descriptive statistics were used to summarize the demographic person interviews occurring within 1 year after diagnosis (median and clinical characteristics of patients stratified by weekly exercise elapse time from diagnosis to interview is 254 days), and men frequency. Survival analysis and the Cox proportional hazards were asked for consent to access medical records and tumor tissue model were used to assess the association between physical collected at biopsy and surgery. Vigorous physical activities were activity and the risk of metastatic–lethal progression, adjusting defined
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