TY - JOUR
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
N1 - Copyright © 2018. Published by Elsevier B.V.
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.
U2 - 10.1016/j.canlet.2018.06.030
DO - 10.1016/j.canlet.2018.06.030
M3 - Article
C2 - 29964205
SN - 0304-3835
VL - 433
SP - 242
EP - 251
JO - Cancer letters
JF - Cancer letters
ER -