title: Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study.
abstract: BACKGROUND
  Survival benefit from surgical debulking of ovarian cancer (OC) is well established, but some women, despite total macroscopic clearance of disease, still have poor prognosis. We aimed to identify biomarkers to predict benefit from conventional surgery.
  
  
  METHODS
  Clinical data from women debulked for high-stage OC were analysed (Hammersmith Hospital, London, UK; 2001-2014). Infinium's HumanMethylation27 array interrogated tumour DNA for differentially methylated CpG sites, correlated to survival, in patients with the least residual disease (RD; Hammersmith Array). Validation was performed using bisulphite pyrosequencing (Charité Hospital, Berlin, Germany cohort) and The Cancer Genome Atlas' (TCGA) methylation data set. Kaplan-Meier curves and Cox models tested survival.
  
  
  RESULTS
  Altogether 803 women with serous OC were studied. No RD was associated with significantly improved overall survival (OS; hazard ratio (HR) 1.25, 95% CI 1.06-1.47; P=0.0076) and progression-free survival (PFS; HR 1.23, 95% CI 1.05-1.43; P=0.012; Hammersmith database n=430). Differentially methylated loci within FGF4, FGF21, MYLK2, MYLK3, MYL7, and ITGAE associated with survival. Patients with the least RD had significantly better OS with higher methylation of MYLK3 (Hammersmith (HR 0.51, 95% CI 0.31-0.84; P=0.01), Charité (HR 0.46, 95% CI 0.21-1.01; P=0.05), and TCGA (HR 0.64, 95% CI 0.44-0.93; P=0.02)).
  
  
  CONCLUSIONS
  MYLK3 methylation is associated with improved OS in patients with the least RD, which could potentially be used to determine response to surgery.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: David L
authors.initials: DL
authors.lastname: Phelps
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Jane V
authors.initials: JV
authors.lastname: Borley
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Kirsty J
authors.initials: KJ
authors.lastname: Flower
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dina
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin, Berlin 10117, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.affiliation: Department of Gynaecology, Virchow Campus, Universitätsmedizin, Berlin, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Braicu
authors.affiliation: Department of Gynaecology, Virchow Campus, Universitätsmedizin, Berlin, Germany.
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.|Department of Gynaecology, Virchow Campus, Universitätsmedizin, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Fotopoulou
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: Wilhelm-Benartzi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Yazbek
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chatterjee
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Jacey
authors.initials: J
authors.lastname: Ip
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Harun
authors.initials: H
authors.lastname: Khan
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Marina-Therese
authors.initials: MT
authors.lastname: Likos-Corbett
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000601:surgery; D018899:CpG Islands; D065426:Cytoreduction Surgical Procedures; D019175:DNA Methylation; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000601:surgery; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009219:Myosin-Light-Chain Kinase / Q000235:genetics*; D018365:Neoplasm, Residual; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000601:surgery; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000601:surgery; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D018570:Risk Assessment / Q000379:methods; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D009219:Myosin-Light-Chain Kinase; C524358:cardiac myosin light chain kinase, human