Novel Methylation-Based Biomarkers May Predict Prostate Cancer Mortality

By: Gavin Calabretta, BS
Posted: Wednesday, December 7, 2022

A group of researchers, including Susan Clark, PhD, of the Garvan Institute of Medical Research, Sydney, Australia, recently sequenced the methylomes of patients with prostate cancer to identify new prognostic biomarkers. According to the team’s findings, which were published in Clinical and Translational Medicine, there appeared to be significant associations between prostate cancer–specific mortality and hypermethylation in several distinct genes.

“There’s a need for men with prostate cancer to have more personalized treatments guided by the nature of their tumors, and they can’t get that without new biomarkers that can better predict the risk of developing the lethal form of the disease,” Professor Clark commented in an institutional press release.

The investigators used whole-genome bisulfite sequencing to compare DNA methylation of radical prostatectomy tissue across 15 patients; they identified 1,420 differentially methylated regions that were associated with prostate cancer–specific mortality. These research findings were compared with public databases, and 18 were selected for the development of a prognostic gene panel; this panel was subsequently validated in an independent cohort of 186 patients.

When the researchers applied the panel to the validation cohort, univariate analysis revealed that hypermethylation at five genomic regions was significantly linked with prostate cancer–specific mortality. These regions were CACNA2D4 (P = .00011), EPHB3 (P = .023), PARP6 (P = .019), TBX1 (P = .0063), and MARCH6 (P = .042), respectively. Particularly, CACNA2D4, which encodes a protein in the voltage-dependent calcium channel complex, was also a significant predictor of poor outcomes in biochemical recurrence (hazard ratio [HR] = 2.18; 95% confidence interval [CI] = 1.4–3.38; P = .0005) and metastatic relapse (HR = 2.64; 95% CI = 1.2–5.83; P = .016), in addition to prostate cancer–specific mortality (HR = 5.84; 95% CI = 2.12–16.13; P = .001). Of note, the study authors found that CACNA2D4 methylation was a better predictor of prostate cancer–specific mortality than International Society of Urological Pathology grade alone (Harrell’s C-index = 0.779 vs. 0.684).