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.
Highlights
Ovarian cancer (OC) is the second most common gynecological cancer and the leading cause of death among gynecological cancers worldwide [1]. 22,240 new cases were estimated for 2013 in the United States, leading to 14,030 deaths from this cancer type [2]
The ability to predict OC outcomes after surgical resection is critical for clinicians, as it would impact the use of adjuvant chemotherapy and radiation therapies
(11/57) for ESR1, 67% (38/57) for HIC1, 28% (16/57) for PGP9.5 and 37% (21/57) for VGF. Each of the latter 4 genes were significantly more methylated in OC than normal (p =,0.05 for each gene)
Summary
Ovarian cancer (OC) is the second most common gynecological cancer and the leading cause of death among gynecological cancers worldwide [1]. 22,240 new cases were estimated for 2013 in the United States, leading to 14,030 deaths from this cancer type [2]. The initial clinical response to platinum-based drugs is a major determinant of outcome for patients with OC. Patients with tumors demonstrating in vitro extreme drug resistance to platinum were found to be at a significantly increased risk for progression and death when treated with standard platinum-based regimens [5]. It is of major significance to identify useful predictive markers indicating platinum sensitivity. These may allow better treatment selection for the 1st line of treatment, possibly allowing better outcome for the platinum resistant patients. Determination of appropriate markers to anticipate response to standard chemotherapeutic or newer biologic agents will allow for improved control and cure rates for OC, as well as selection of adjuvant therapy or identification of patients appropriate for specific clinical trials. An independent prognostic indicator of OC survival would be invaluable to physicians and patients in selecting treatment options
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