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

5 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Maldonado, L., Brait, M., Izumchenko, E., Begum, S., Chatterjee, A., Sen, T., Loyo, M., Barbosa, A., Poeta, M. L., Makarev, E., Zhavoronkov, A., Fazio, V. M., Angioli, R., Rabitti, C., Ongenaert, M., Van Criekinge, W., Noordhuis, M. G., de Graeff, P., Wisman, G. B. A., ... 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