title: Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  CpG sites at contiguous genomic locations within the MSX1 gene 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 decreased MSX1 gene expression. MSX1 expression 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 reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression.
  
  
  
  Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity. Clin Cancer Res; 22(12); 3097-104. ©2016 AACR.
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Nair A
authors.initials: NA
authors.lastname: Bonito
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Borley
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: Wilhelm-Benartzi
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London W12 0NN, UK.|Institute of Cancer Research, Sutton, London SM2 5NG, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000627:therapeutic use*; D018899:CpG Islands / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D019175:DNA Methylation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051957:MSX1 Transcription Factor / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D034741:RNA, Small Interfering; D002945:Cisplatin