DNA methyltransferase 3b (DNMT3b), tumor tissue DNA methylation, Gleason score, and prostate cancer mortality: Investigating causal relationships

摘要

Purpose Aberrant DNA methylation plays a role in prostate cancer progression. We studied the relationships among DNA methyltransferase (DNMT) genotype, DNA methylation, Gleason score, and mortality in two cohorts of prostate cancer patients, previously reported with associations between DNA methylation in GSTP1, APC, and RUNX3 and prostate cancer mortality. Herein, we considered possible causal relationships between the studied variables, assuming that (1) DNMT activity affects tumor tissue methylation, (2) methylation status affects tumor morphology, and thus the Gleason score, and (3) DNA methylation affects mortality via Gleason score. Methods The cohorts comprised 438 patients diagnosed at one Italian pathology ward before 1997, with DNA obtained from paraffin-embedded tumor tissues. The polymorphism rs406193 in the DNMT3b gene was assessed by allele discrimination in real-time PCR. According to the assumed causal model, we analyzed the effects of rs406193 (T carriers vs others) on the Gleason score without adjusting for gene methylation, and the effects of rs406193 on gene methylation and prostate cancer mortality without adjusting for Gleason score. Results We found no evidence of association between T carriers and the number of methylated genes. However, T carriers had reduced risk of a Gleason score 8? (odds ratio = 0.57, 95 % CI 0.39-0.85), and a hazard ratio of 0.81 (0.61-1.09) of dying from prostate cancer, which would have been erroneously estimated of 0.93 if adjusted for Gleason score. Conclusions These findings provide clues on the role of a DNMT3b SNP in prostate cancer progression and illustrate the importance of considering possible causal relationships in the analyses.