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 ZeeMohammad O. Hoque

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)242-251
Number of pages10
JournalCancer Letters
Volume433
DOIs
StatePublished - Oct 1 2018

Fingerprint

Epigenomics
Ovarian Neoplasms
Methylation
Epithelium
Cystadenoma
Genes
Epithelial Cells
Genome
Cell Line
Growth
Neoplasms

Keywords

  • Biomarkers
  • DNA methylation
  • Epigenetics
  • GULP1
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Maldonado, L., Brait, M., Izumchenko, E., Begum, S., Chatterjee, A., Sen, T., ... Hoque, M. O. (2018). Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1. Cancer Letters, 433, 242-251. https://doi.org/10.1016/j.canlet.2018.06.030

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.

In: Cancer Letters, Vol. 433, 01.10.2018, p. 242-251.

Research output: Contribution to journalArticle

Maldonado, L, Brait, M, Izumchenko, E, Begum, S, Chatterjee, A, Sen, T, Loyo, M, Barbosa, A, Poeta, ML, Makarev, E, Zhavoronkov, A, Fazio, VM, Angioli, R, Rabitti, C, Ongenaert, M, Van Criekinge, W, Noordhuis, MG, de Graeff, P, Wisman, GBA, van der Zee, AGJ & Hoque, MO 2018, 'Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1', Cancer Letters, vol. 433, pp. 242-251. https://doi.org/10.1016/j.canlet.2018.06.030
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. / Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1. In: Cancer Letters. 2018 ; Vol. 433. pp. 242-251.
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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.",
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AU - Maldonado, Leonel

AU - Brait, Mariana

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AU - Begum, Shahnaz

AU - Chatterjee, Aditi

AU - Sen, Tanusree

AU - Loyo, Myriam

AU - Barbosa, Alvaro

AU - Poeta, Maria Luana

AU - Makarev, Eugene

AU - Zhavoronkov, Alex

AU - Fazio, Vito M.

AU - Angioli, Roberto

AU - Rabitti, Carla

AU - Ongenaert, Mate

AU - Van Criekinge, Wim

AU - Noordhuis, Maartje G.

AU - de Graeff, Pauline

AU - Wisman, G. Bea A.

AU - van der Zee, Ate G.J.

AU - Hoque, Mohammad O.

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