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

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

Otolaryngology

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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.

Original language	English (US)
Pages (from-to)	242-251
Number of pages	10
Journal	Cancer Letters
Volume	433
DOIs	https://doi.org/10.1016/j.canlet.2018.06.030
State	Published - Oct 1 2018

Keywords

Biomarkers
DNA methylation
Epigenetics
GULP1
Ovarian cancer

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2018.06.030

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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

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

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title = "Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1",

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",

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

note = "Publisher Copyright: {\textcopyright} 2018",

year = "2018",

month = oct,

day = "1",

doi = "10.1016/j.canlet.2018.06.030",

language = "English (US)",

volume = "433",

pages = "242--251",

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T1 - Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1

AU - Maldonado, Leonel

AU - Brait, Mariana

AU - Izumchenko, Evgeny

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.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - Biomarkers

KW - DNA methylation

KW - Epigenetics

KW - GULP1

KW - Ovarian cancer

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DO - 10.1016/j.canlet.2018.06.030

M3 - Article

C2 - 29964205

AN - SCOPUS:85049640018

SN - 0304-3835

VL - 433

SP - 242

EP - 251

JO - Cancer Letters

JF - Cancer Letters

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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