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

Leonel Maldonado; Mariana Brait; Evgeny Izumchenko; Shahnaz Begum; Aditi Chatterjee; Tanusree Sen; Myriam Loyo; Alvaro Barbosa; Maria Luana Poeta; Eugene Makarev; Alex Zhavoronkov; Vito M Fazio; Roberto Angioli; Carla Rabitti; Mate Ongenaert; Wim Van Criekinge; Maartje G Noordhuis; Pauline de Graeff; G Bea A Wisman; Ate G J van der Zee; Mohammad O Hoque

doi:10.1016/j.canlet.2018.06.030

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

Cancer Lett. 2018 Oct 1:433:242-251. doi: 10.1016/j.canlet.2018.06.030. Epub 2018 Jun 28.

Authors

Leonel Maldonado¹, Mariana Brait², Evgeny Izumchenko², Shahnaz Begum³, Aditi Chatterjee⁴, Tanusree Sen², Myriam Loyo⁵, Alvaro Barbosa⁶, Maria Luana Poeta⁷, Eugene Makarev⁸, Alex Zhavoronkov⁸, Vito M Fazio⁹, Roberto Angioli¹⁰, Carla Rabitti¹¹, Mate Ongenaert¹², Wim Van Criekinge¹², Maartje G Noordhuis¹³, Pauline de Graeff¹⁴, G Bea A Wisman¹⁴, Ate G J van der Zee¹⁴, Mohammad O Hoque¹⁵

Affiliations

¹ 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.
² Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁴ 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.
⁵ 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.
⁶ Department of Pathology, Hospital San Jose Tec de Monterrey, Monterrey, Nuevo Leon, Mexico.
⁷ Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
⁸ Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
⁹ 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.
¹⁰ Department of Gynecology, University Campus Bio-Medico of Rome, Rome, Italy.
¹¹ Department of Pathology, University Campus Bio-Medico of Rome, Rome, Italy.
¹² Department of Mathematical Modeling, Statistics and Bio-Informatics, Ghent University, Ghent, Belgium.
¹³ 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.
¹⁴ Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁵ 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. Electronic address: mhoque1@jhmi.edu.

PMID: 29964205
DOI: 10.1016/j.canlet.2018.06.030

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, TGFβ2), 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.

Keywords: Biomarkers; DNA methylation; Epigenetics; GULP1; Ovarian cancer.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adult
Aged
Aged, 80 and over
Carcinoma, Ovarian Epithelial / genetics*
Carcinoma, Ovarian Epithelial / pathology
Cell Line, Tumor
Cell Proliferation / genetics
Cystadenoma / genetics
DNA Methylation / genetics*
Epigenesis, Genetic / genetics
Epithelium / pathology
Female
Gene Expression Regulation, Neoplastic / genetics*
Gene Silencing*
Humans
Middle Aged
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / pathology

Substances

Adaptor Proteins, Signal Transducing
GULP1 protein, human