Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.

Many epigenetically inactivated genes involved in ovarian cancer (OC) development and progression remain to be identified. In this study we undertook an integrated approach that consisted of identification of genome-wide expression patterns of primary OC samples and normal ovarian surface epithelium along with a pharmacologic unmasking strategy using 3 OC and 3 immortalized normal ovarian epithelial cell lines. Our filtering scheme identified 43 OC specific methylated genes and among the 5 top candidates (GULP1, CLIP4, BAMBI, NT5E, TGFß2), we performed extended studies of GULP1. In a training set, we identified GULP1 methylation in 21/61 (34%) of cases with 100% specificity. In an independent cohort, the observed methylation was 40% (146/365) in OC, 12.5% (2/16) in borderline tumors, 11% (2/18) in cystadenoma and 0% (0/13) in normal ovarian epithelium samples. GULP1 methylation was associated with clinicopathological parameters such as stage III/IV (p = 0.001), poorly differentiated grade (p = 0.033), residual disease (p < 0.0003), worse overall (p = 0.02) and disease specific survival (p = 0.01). Depletion of GULP1 in OC cells led to increased pro-survival signaling, inducing survival and colony formation, whereas reconstitution of GULP1 negated these effects, suggesting that GULP1 is required for maintaining cellular growth control.

Funciones ejecutivas, rasgos de personalidad e impulsividad en condenados por acceso carnal violento / Executive functions, personality traits and impulse-control in convicted of violent-carnal access

Resumen Se evaluaron las funciones ejecutivas, los rasgos de personalidad y la impulsividad en 29 hombres condenados por acceso carnal violento y recluidos en la cárcel Modelo Bogotá-Colombia, mediante un cuestionario sociodemográfico, la Batería Neuropsicológica de Funciones Ejecutivas y Lóbulos Frontales (banfe), la Escala de Impulsividad de Barratt (bis 11) y el Cuestionario Exploratorio de Personalidad (ceper iii), con el fin de identificar relaciones entre sus puntuaciones. Los resultados evidencian que el 41,4 % de los participantes mostró puntuaciones diagnósticas en al menos un factor de impulsividad o de funciones ejecutivas. El 79,3 % de los participantes evidenció al menos un rasgo de personalidad, siendo los del tipo obsesivo-compulsivo, pasivo-agresivo y dependiente, los de mayor frecuencia. Se identificaron algunas correlaciones entre los factores de impulsividad, los rasgos de personalidad y las funciones ejecutivas. Estos hallazgos se discuten en términos de la relación entre los constructos evaluados, la agresión sexual y sus implicaciones sobre el tratamiento penitenciario.

Abstract Executive-functions, personality traits and impulsivity were evaluated in 29 men convicted of violent-carnal access in the Modelo Jail (Bogota-Colombia), through a sociodemographic questionnaire, the Neuropsychological Battery for Executive Functions and Frontal Lobes (banfe), the Barratt Impulsivity Scale (bis 11) and the Personality Exploratory Questionnaire (ceper III), in order to identify relationships between their scores. The results show that 41,4 % of the participants showed diagnostic scores in at least one factor of impulsivity or executive functions. At least one personality trait was observed in 79,3 % of the participants; obsessive-compulsive, passive-aggressive and dependent traits were those with highest frequency. Some correlations were identified between impulsivity factors, personality traits and executive functions. These findings are discussed in terms of the relationship between the constructs evaluated, sexual assault and their implications on the treatment of prisioners.

Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.

PURPOSE: To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC). EXPERIMENTAL DESIGN: PH 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. RESULTS: PH 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. CONCLUSIONS: Our 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.