title: Breast cancer metastasis suppressor-1 promoter methylation in cell-free DNA provides prognostic information in non-small cell lung cancer.
abstract: BACKGROUND
  Breast-cancer metastasis suppressor 1 (BRMS1) gene encodes for a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without blocking orthotropic tumour growth. The aim of the present study was to evaluate for the first time the prognostic significance of BRMS1 promoter methylation in cell-free DNA (cfDNA) circulating in plasma of non-small cell lung cancer (NSCLC) patients. Towards this goal, we examined the methylation status of BRMS1 promoter in NSCLC tissues, matched adjacent non-cancerous tissues and corresponding cfDNA as well as in an independent cohort of patients with advanced NSCLC and healthy individuals.
  
  
  METHODS
  Methylation of BRMS1 promoter was examined in 57 NSCLC tumours and adjacent non-cancerous tissues, in cfDNA isolated from 48 corresponding plasma samples, in cfDNA isolated from plasma of 74 patients with advanced NSCLC and 24 healthy individuals.
  
  
  RESULTS
  The BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and in corresponding cfDNA (47.9%) but not in cfDNA from healthy individuals (0%), while it was also highly methylated in cfDNA from advanced NSCLC patients (63.5%). In operable NSCLC, Kaplan-Meier estimates were significantly different in favour of patients with non-methylated BRMS1 promoter in cfDNA, concerning both disease-free interval (DFI) (P=0.048) and overall survival (OS) (P=0.007). In advanced NSCLC, OS was significantly different in favour of patients with non-methylated BRMS1 promoter in their cfDNA (P=0.003). Multivariate analysis confirmed that BRMS1 promoter methylation has a statistical significant influence both on operable NSCLC patients' DFI time and OS and on advanced NSCLC patients' PFS and OS.
  
  
  CONCLUSIONS
  Methylation of BRMS1 promoter in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumour biomarker.
authors.affiliation: 1] Analysis of Circulating Tumor Cells Lab, Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, 15771 Athens, Greece [2] Department of Medical Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: I
authors.initials: I
authors.lastname: Balgkouranidou
authors.affiliation: Analysis of Circulating Tumor Cells Lab, Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, 15771 Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Chimonidou
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Medical School, University of Crete, Heraklion, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Milaki
authors.affiliation: 7th Pulmonology Clinic, 'Sotiria' General Hospital for Chest Diseases, 11526 Athens, Greece.
authors.forename: E G
authors.initials: EG
authors.lastname: Tsarouxa
authors.affiliation: Department of Medical Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: S
authors.initials: S
authors.lastname: Kakolyris
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, University of Kansas Cancer Center, 3901 Rainbow Boulevard, MS-1071, Kansas City, KS 66160, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Welch
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Medical School, University of Crete, Heraklion, Greece.
authors.forename: V
authors.initials: V
authors.lastname: Georgoulias
authors.affiliation: Analysis of Circulating Tumor Cells Lab, Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, 15771 Athens, Greece.
authors.forename: E S
authors.initials: ES
authors.lastname: Lianidou
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics / Q000302:isolation & purification; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins
chemical_list: C410024:BRMS1 protein, human; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012097:Repressor Proteins