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@article{Bonito:2016:10.1158/1078-0432.CCR-15-1669,
author = {Bonito, NA and Borley, J and Wilhelm-Benartzi, CS and Ghaem-Maghami, S and Brown, R},
doi = {10.1158/1078-0432.CCR-15-1669},
journal = {Clinical Cancer Research},
pages = {3097--3104},
title = {Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.},
url = {http://dx.doi.org/10.1158/1078-0432.CCR-15-1669},
volume = {22},
year = {2016}
}
TY - JOUR
AB - PURPOSE: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. EXPERIMENTAL DESIGN: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. RESULTS: CpG sites at contiguous genomic locations within theMSX1gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P< 0.05,q< 0.05,n= 78), have poor RECIST response (P< 0.05,q< 0.05,n= 61), and are associated with PFS in an independent cohort (n= 146). A decrease in methylation at these CpG sites correlates with decreasedMSX1gene expression.MSX1expression is associated with PFS (HR, 0.92; 95% CI, 0.85-0.99;P= 0.029;n= 309). Cisplatin-resistant ovarian cancer cell lines have reducedMSX1expression, andMSX1overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression. CONCLUSIONS: Hypomethylation of CpG sites within theMSX1gene is associated with resistant HGSOC disease at presentation and identifies expression ofMSX1as conferring platinum drug sensitivity.Clin Cancer Res; 1-8. ©2016 AACR.
AU - Bonito,NA
AU - Borley,J
AU - Wilhelm-Benartzi,CS
AU - Ghaem-Maghami,S
AU - Brown,R
DO - 10.1158/1078-0432.CCR-15-1669
EP - 3104
PY - 2016///
SN - 1557-3265
SP - 3097
TI - Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.
T2 - Clinical Cancer Research
UR - http://dx.doi.org/10.1158/1078-0432.CCR-15-1669
VL - 22
ER -
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