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

Abstract

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.

Association of MGMT promoter methylation with tumorigenesis features in patients with ovarian cancer: A systematic meta‐analysis

“…Our initial search yielded a total of 81 potential studies based on the above described search strategy. In the end, 10 case–control studies involving 910 ovarian tissue samples (Agostini et al., ; An et al., ; Brait et al., ; Chmelarova et al., ; Furlan et al., ; Makarla et al., ; Rimel, Huettner, Powell, Mutch, & Goodfellow, ; Roh et al., ; Shilpa et al., ; Wu et al., ) were included in the current meta‐analysis (Figure ). The main characteristics of eligible studies were extracted and shown in Table .…”

RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer

“…Further genome‐wide analyses are necessary to improve the sensitivity of the marker set. Of interest might be a combined analyses of poor prognosis markers ( i.e., RUNX3 , CAMK2N1 ) and methylation markers associated with good prognosis ( VGF , PGP9.5) . If such marker sets are successfully validated they may enable the stratification of patients and the selective maintenance treatment with angiogenesis inhibitors, for example, Bevazicumab.…”

Epigenetic inactivation of VGF associated with Urothelial Cell Carcinoma and its potential as a non-invasive biomarker using urine

“…Similarly we also reported previously that UCC can be detected using urine sediment DNA with high sensitivity and specificity [27] and methylation patterns are consistent in primary UCC tissues and urine. Here we found high frequency of methylation of VGF in the urine of UCC cases [8/20(40%)] than controls [1/20(5%)]. We were not able to test methylation status of matched tumor-urine samples due to the lack of available samples.…”