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Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.
Maldonado, Leonel; Brait, Mariana; Izumchenko, Evgeny; Begum, Shahnaz; Chatterjee, Aditi; Sen, Tanusree; Loyo, Myriam; Barbosa, Alvaro; Poeta, Maria Luana; Makarev, Eugene; Zhavoronkov, Alex; Fazio, Vito M; Angioli, Roberto; Rabitti, Carla; Ongenaert, Mate; Van Criekinge, Wim; Noordhuis, Maartje G; de Graeff, Pauline; Wisman, G Bea A; van der Zee, Ate G J; Hoque, Mohammad O.
Afiliación
  • Maldonado L; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, University of South Alabama Medical Center, Mobile, AL, USA.
  • Brait M; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Izumchenko E; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Begum S; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
  • Chatterjee A; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.
  • Sen T; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Loyo M; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.
  • Barbosa A; Department of Pathology, Hospital San Jose Tec de Monterrey, Monterrey, Nuevo Leon, Mexico.
  • Poeta ML; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
  • Makarev E; Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
  • Zhavoronkov A; Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
  • Fazio VM; Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Rome, Italy; Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
  • Angioli R; Department of Gynecology, University Campus Bio-Medico of Rome, Rome, Italy.
  • Rabitti C; Department of Pathology, University Campus Bio-Medico of Rome, Rome, Italy.
  • Ongenaert M; Department of Mathematical Modeling, Statistics and Bio-Informatics, Ghent University, Ghent, Belgium.
  • Van Criekinge W; Department of Mathematical Modeling, Statistics and Bio-Informatics, Ghent University, Ghent, Belgium.
  • Noordhuis MG; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • de Graeff P; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Wisman GBA; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • van der Zee AGJ; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Hoque MO; Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cancer Lett ; 433: 242-251, 2018 10 01.
Article en En | MEDLINE | ID: mdl-29964205
ABSTRACT
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Regulación Neoplásica de la Expresión Génica / Metilación de ADN / Silenciador del Gen / Proteínas Adaptadoras Transductoras de Señales / Carcinoma Epitelial de Ovario Límite: Adult / Aged / Aged80 / Female / Humans / Middle aged Idioma: En Revista: Cancer Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Regulación Neoplásica de la Expresión Génica / Metilación de ADN / Silenciador del Gen / Proteínas Adaptadoras Transductoras de Señales / Carcinoma Epitelial de Ovario Límite: Adult / Aged / Aged80 / Female / Humans / Middle aged Idioma: En Revista: Cancer Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos