A<i>IM1</i> promoter hypermethylation as a predictor of decreased risk of recurrence following radical prostatectomy

Rosenbaum, Eli; Begum, Shahnaz; Brait, Mariana; Zahurak, Marianna; Maldonado, Leonel; Mangold, Leslie A.; Eisenberger, Mario A.; Epstein, Jonathan I.; Partin, Alan W.; Sidransky, David; Hoque, Mohammad O.

doi:10.1002/pros.22461

Cited by 19 publications

(9 citation statements)

References 28 publications

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“…In the study by Tokumaru et al [26] PGP9.5 was found to have a high frequency of PH in a large panel of primary tumors, and their data support the notion that this gene is a TSG that is inactivated by PH or gene deletion in several types of human cancers. Some genes were described as hypermethylated in other cancer types, these include SSBP2 , [27], CCNA1 [28], [29], AIM1 [30], VGF [17], FKBP4 [31], and we decided to evaluate their promoter methylation status in ovarian tissues samples.…”

Section: Discussionmentioning

confidence: 99%

Association of Promoter Methylation of VGF and PGP9.5 with Ovarian Cancer Progression

et al. 2013

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PurposeTo elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC).Experimental DesignPH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated.ResultsPH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI) = 0.42–0.84, p = 0.004), and 0.73 (95%CI = 0.55–0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39–0.82, p = 0.003) and 0.72 (95%CI 0.54–0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43–0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41–0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth.ConclusionsOur results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.

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Section: Discussionmentioning

confidence: 99%

Association of Promoter Methylation of VGF and PGP9.5 with Ovarian Cancer Progression

et al. 2013

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“…In recent years, other variable DNA methylation alterations in neoplastic tissue samples have been also associated with the prediction of PSA recurrence after RP [10,17,18,19,20,21,22,23,24]. These studies have identified new potential tumor markers including methylation of PITX2 , HOXD3 , APC , TGFβ2 , RASSF1A , ANEP , PCDH10 , ZNF132 , TDRD1 , AOX1 , C1orf114 , GAS6 , HAPLN3 , KLF8 , MOB3B , CCND2 , PTGS2 , RARB , SRD5A2 and CYP11A1 , thus emerging as new predictors of BCR particularly in high-risk clinically localized disease.…”

Section: Discussionmentioning

confidence: 99%

A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

Angulo

López

Dorado³

et al. 2016

Urol Int

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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.

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“…16,17,21,25,26 Our group recently reported that decreased promoter methylation of AIM1 in PCa was associated with shorter time to progression in a cohort of 95 patients with only Gleason sum 3 + 4 = 7. 27 None of these genes were significantly associated with PCa recurrence in the current study in part due to tumor heterogeneity and other associated factors, such as the methylation analysis technique, environmental and endogenous factors, and, as mentioned, population size and heterogeneity.…”

Section: Discussionmentioning

confidence: 54%

GSTP1 Promoter Methylation is Associated with Recurrence in Early Stage Prostate Cancer

et al. 2014

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Purpose Recurrent prostate cancer remains a major problem. Staging, grading and prostate specific antigen level at surgery are helpful but still imperfect predictors of recurrence. For this reason there is an imperative need for additional biomarkers that add to the prediction of currently used prognostic factors. Materials and Methods We evaluated the extent of promoter methylation of genes previously reported as aberrantly methylated in prostate cancer (AIM1, APC, CCND2, GPX3, GSTP1, MCAM, RARβ2, SSBP2 and TIMP3) by quantitative fluorogenic methylation-specific polymerase chain reaction. We used cancer tissue from a nested case-control study of 452 patients surgically treated for prostate cancer. Recurrence cases and controls were compared and the association between methylation extent and recurrence risk was estimated by logistic regression adjusting for patient age at prostatectomy, prostatectomy year, stage, grade, surgical margins and preprostatectomy prostate specific antigen. All statistical tests were 2-sided with p ≤0.05 considered statistically significant. Results The extent of GSTP1 methylation was higher in patients with recurrence than in controls (p = 0.01), especially patients with early disease, ie organ confined or limited extraprostatic extension (p = 0.001). After multivariate adjustment GSTP1 promoter methylation at or above the median was associated with an increased risk of recurrence, including in men with early disease (each p = 0.05). Conclusions Greater GSTP1 promoter methylation in cancer tissue was independently associated with the risk of recurrence in patients with early prostate cancer. This suggests that GSTP1 promoter methylation may be a potential tissue based recurrence marker.

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AIM1 promoter hypermethylation as a predictor of decreased risk of recurrence following radical prostatectomy

Cited by 19 publications

References 28 publications

Association of Promoter Methylation of VGF and PGP9.5 with Ovarian Cancer Progression

Association of Promoter Methylation of VGF and PGP9.5 with Ovarian Cancer Progression

A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

GSTP1 Promoter Methylation is Associated with Recurrence in Early Stage Prostate Cancer

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