Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.
File(s)
Accepted version
Author(s)
Bonito, NA
Borley, J
Wilhelm-Benartzi, CS
Ghaem-Maghami, S
Brown, R
Type
Journal Article
Abstract
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.
Date Issued
2016-01-13
Date Acceptance
2015-12-24
Citation
Clinical Cancer Research, 2016, 22 (12), pp.3097-3104
ISSN
1557-3265
Publisher
American Association for Cancer Research
Start Page
3097
End Page
3104
Journal / Book Title
Clinical Cancer Research
Volume
22
Issue
12
Copyright Statement
© 2016 American Association for Cancer Research.
Sponsor
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Cancer Research UK
Identifier
PII: 1078-0432.CCR-15-1669
Grant Number
C536/A13086
RD205
RDEMC 79560
C42671 / A12993
Subjects
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status
Published