MYC exon 3 DNA methylation in peripheral blood and the risk of aggressive prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial

Introduction : Our group previously reported that higher DNA methylation at two CpG sites in MYC exon 3 in peripheral blood was associated with a higher risk of aggressive prostate cancer (Barry et al, Br J Cancer 2017). Here we aimed to assess if our findings for these CpG sites would replicate in an independent group of men. Methods : Using pre-diagnostic blood samples, we conducted a nested prostate cancer case-control study among non-Hispanic White men in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial who were not included in our previous study in PLCO. Cases comprised 251 men who were diagnosed with incident aggressive prostate cancer (stage III or IV or a total Gleason score>=8), and controls comprised 497 men without a previous history of prostate cancer. The controls were individually matched to the cases on several factors, including age at blood draw (+/- 3 yrs), calendar year of blood draw (+/- 3 years), study year of blood draw, sample type (i.e., whole blood or buffy coat), and the source of the DNA (i.e., available DNA from previous genotyping efforts in PLCO or new extractions). Percent DNA methylation at the CpG sites of interest in the exon 3 region of MYC , denoted as CpG 214 (GRCh37/hg19 coordinate: Chr8:128753154) and CpG 215 (Chr8:128753187), was quantified using pyrosequencing on bisulfite-treated DNA. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for DNA methylation levels, modeled as a continuous variable, in relation to aggressive prostate cancer. We also conducted a meta-analysis to combine the results from our two studies (total of 423 aggressive prostate cancer cases). Results : For both CpG 214 and 215, we observed an elevated risk of aggressive prostate cancer with each unit increase of DNA methylation (for CpG 214, OR=1.05, 95% CI: 0.99-1.12, and for CpG 215, OR=1.03, 95% CI: 0.97-1.09). We observed similar patterns that were statistically significant for both CpG sites when meta-analyzing these results with our previous study (for CpG 214, OR=1.06, 95% CI: 1.02-1.10, and for CpG 215, OR=1.05, 95% CI: 1.01-1.10). Conclusions: Adding to the literature on the role of MYC in prostate carcinogenesis, findings support that higher pre-diagnostic DNA methylation levels in MYC exon 3 in peripheral blood are associated with a higher risk of aggressive prostate cancer among non-Hispanic White men. Further study is needed in more diverse populations.