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

(2018) CANCER LETTERS. 433. p.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, TGF beta 2, 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
GULP1, Ovarian cancer, Epigenetics, Biomarkers, DNA methylation, DNA METHYLATION BIOMARKERS, ADAPTER PROTEIN GULP, APOPTOTIC CELLS, CAENORHABDITIS-ELEGANS, PROMOTER METHYLATION, BLADDER-CANCER, C-ELEGANS, GROWTH, ENGULFMENT, EXPRESSION

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MLA
Maldonado, Leonel et al. “Integrated Transcriptomic and Epigenomic Analysis of Ovarian Cancer Reveals Epigenetically Silenced GULP1.” CANCER LETTERS 433 (2018): 242–251. Print.
APA
Maldonado, L., Brait, M., Izumchenko, E., Begum, S., Chatterjee, A., Sen, T., Loyo, M., et al. (2018). Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1. CANCER LETTERS, 433, 242–251.
Chicago author-date
Maldonado, Leonel, Mariana Brait, Evgeny Izumchenko, Shahnaz Begum, Aditi Chatterjee, Tanusree Sen, Myriam Loyo, et al. 2018. “Integrated Transcriptomic and Epigenomic Analysis of Ovarian Cancer Reveals Epigenetically Silenced GULP1.” Cancer Letters 433: 242–251.
Chicago author-date (all authors)
Maldonado, Leonel, 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, Maté Ongenaert, Wim Van Criekinge, Maartje G Noordhuis, Pauline de Graeff, G Bea A Wismann, Ate GJ van der Zee, and Mohammad O Hoque. 2018. “Integrated Transcriptomic and Epigenomic Analysis of Ovarian Cancer Reveals Epigenetically Silenced GULP1.” Cancer Letters 433: 242–251.
Vancouver
1.
Maldonado L, Brait M, Izumchenko E, Begum S, Chatterjee A, Sen T, et al. Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1. CANCER LETTERS. 2018;433:242–51.
IEEE
[1]
L. Maldonado et al., “Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1,” CANCER LETTERS, vol. 433, pp. 242–251, 2018.
@article{8609168,
  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, TGF beta 2, 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.},
  author       = {Maldonado, Leonel and Brait, Mariana and Izumchenko, Evgeny and Begum, Shahnaz and Chatterjee, Aditi and Sen, Tanusree and Loyo, Myriam and Barbosa, Alvaro and Poeta, Maria Luana and Makarev, Eugene and Zhavoronkov, Alex and Fazio, Vito M and Angioli, Roberto and Rabitti, Carla and Ongenaert, Maté and Van Criekinge, Wim and Noordhuis, Maartje G and de Graeff, Pauline and Wismann, G Bea A and van der Zee, Ate GJ and Hoque, Mohammad O},
  issn         = {0304-3835},
  journal      = {CANCER LETTERS},
  keywords     = {GULP1,Ovarian cancer,Epigenetics,Biomarkers,DNA methylation,DNA METHYLATION BIOMARKERS,ADAPTER PROTEIN GULP,APOPTOTIC CELLS,CAENORHABDITIS-ELEGANS,PROMOTER METHYLATION,BLADDER-CANCER,C-ELEGANS,GROWTH,ENGULFMENT,EXPRESSION},
  language     = {eng},
  pages        = {242--251},
  title        = {Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1},
  url          = {http://dx.doi.org/10.1016/j.canlet.2018.06.030},
  volume       = {433},
  year         = {2018},
}

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