A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

Abstract

Purpose: Detection of DNA hypermethylation is emerging as a novel molecular biomarker for different malignancies. We intend to define whether a hypermethylation profile of patients with prostate cancer (PCa) predicts biochemical recurrence (BCR) after radical prostatectomy (RP). Material and Methods: Genome-wide methylation analysis was performed using the GoldenGate Methylation Cancer Panel-I (Illumina, Inc.) on 10 normal prostate tissues and 58 tumor samples from patients treated by RP followed for prostate-specific antigen (PSA) failure (>0.4 ng/ml) and disease progression. Patients were classified on the basis of D'Amico criteria according to clinical staging, PSA at diagnosis and Gleason score after pathologist review. Hypermethylation status of 1505 CpGs present in the promoter region of 807 genes was studied. Hierarchical clustering analysis was performed and relationships with outcome were investigated using log-rank analysis and Cox regression model. Results: We found 28 genes significantly hypermethylated in >20% of the tumors analyzed. Four clusters of patients were characterized by their DNA methylation profile, one at higher risk to develop BCR (p = 0.005). Multivariate analysis revealed patients in this cluster (HR 2.56), and high-risk patients (HR 4.34) according to D'Amico classification were independent predictors of BCR after prostatectomy. From the selected genes MT1A, ALOX12, GSTM2, APC, MYCL2 and RARB hypermethylation predicted BCR and GSTM2 (HR 3.78) and MYCL2 hypermethylation (HR 2.71) did so independently. Conclusion: Epigenetic silencing of GSTM2 and MYCL2 comprise novel molecular markers to predict BCR after surgery for medium- and high-risk localized PCa undergoing surgical treatment and hypermethylation of these genes could be incorporated to the clinical and pathological factors defining the patient at higher risk of PSA failure after prostatectomy. The limitation of the study is that no independent validation cohort is analysed.

Epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy

“…Evidence from these studies suggests that hypermethylation of PITX2 , GSTP1 , and APC is associated with more aggressive PCa and disease prognosis [ 11 , 12 ]. Some other prior studies have focused on larger sets of CpG sites across the genome and identified different panels of CpG biomarkers for distinguishing more from less aggressive prostate tumors [ 13 – 18 ]. For example, in a previous epigenome-wide analysis from our group, we identified a panel of methylation biomarkers for predicting metastatic-lethal PCa [ 18 ].…”

Identification of key DNA methylation-driven genes in prostate adenocarcinoma: an integrative analysis of TCGA methylation data

“…In terms of GSTM2, Angulo et al [21] revealed that GSTM2 hypermethylation could be used to predict biochemical recurrence after radical prostatectomy, which suggested that epigenetic silencing of GSTM2 played an important role in involving biochemical recurrence. Plus, Ashour et al [22] demonstrated that GSTM2 was hypermethylated in PCa and was simultaneously methylated in 40.9% if the PCa, which revealed that epigenetic silencing of GSTM2 is a common event in PCa.…”

Advances in Prognostic Methylation Biomarkers for Prostate Cancer

“…The second study using the GoldenGate Cancer Panel reported that a gene hypermethylation profile based on hierarchical clustering of patients (see Table 2 for details), as well as hypermethylation at individual markers GSTM2 and MCLY2 , independently predicted BCR risk. The concurrent methylation of the two markers was also associated with PCa death, however no further validation of the study findings in a separate independent cohort was conducted [ 130 ].…”

“…= average, CAPRA-S = Cancer of the Prostate Risk Assessment Score; CRPC = Castration-Resistant Prostate Cancer; GS = Gleason Score; HR = hazard ratio; IDC/C = Intraductal Carcinoma and Cribriform Architecture; M = multivariate analysis; NA = not applicable; non-sig = nonsignificant; ns = not specified; OR = odds ratio; pAUC = partial area under the cure; PCa = prostate cancer; PMR = percent methylated ratio; PSA = prostate- specific antigen; RT = radiotherapy; U = univariate analysis. Definitions: BCR: Biochemical recurrence: PSA elevations ≥ 0.2n g/mL post-RP, except [ 130 ] > 0.4 ng/mL and [ 131 ] > 0.07 ng/mL; clinical recurrence = local recurrence or metastatic relapse; good prognosis: organ-confined disease (pT2) and lack of BCR for at least 5 years; local recurrence: cancer observed on prostatic bed, confirmed by histological analysis of biopsies; metastatic relapse: metastatic deposits (visceral, bony metastasis) confirmed by positive biopsies or cT/bone scans; metastatic-lethal progression = metastatic relapse or PCa death; pathological T-stage: tumour staging based on pathological examination of surgically removed prostate tissue; PCa death: prostate cancer-specific death; poor prognosis: systemic presence of metastatic disease, indicated by recurrence within 3 years and no response to local radiation therapy; progression: either of BCR, metastatic relapse or PCa death; recurrence: either of BCR, local recurrence or metastatic relapse. a All studies are on prostate cancer tissues from radical prostatectomy, unless specified.…”