title: Aberrant promoter methylation of caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC.
abstract: OBJECTIVE
  Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancer-associated gene loci and correlated results with clinical outcomes.
  
  
  METHODS
  We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.
  
  
  RESULTS
  Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance  = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03-0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.
  
  
  CONCLUSIONS
  CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.
authors.affiliation: Atlanta VA Medical Center, Atlanta, Georgia, United States of America; Departments of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Brodie
authors.affiliation: Departments of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Lombardo
authors.affiliation: Departments of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, Georgia, United States of America.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Department of Human Genetics, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, Georgia, United States of America.
authors.forename: Khanjan
authors.initials: K
authors.lastname: Gandhi
authors.affiliation: Atlanta VA Medical Center, Atlanta, Georgia, United States of America; Department of Pathology, School of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Shaojin
authors.initials: S
authors.lastname: You
authors.affiliation: Departments of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Departments of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Marcus
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Vertino
authors.affiliation: Atlanta VA Medical Center, Atlanta, Georgia, United States of America; Departments of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Johann C
authors.initials: JC
authors.lastname: Brandes
mesh_terms: D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D051242:Caveolin 1 / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004338:Drug Combinations; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D015999:Multivariate Analysis; D017671:Platinum Compounds / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D012044:Regression Analysis; D012189:Retrospective Studies; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001952:Bridged-Ring Compounds; D051242:Caveolin 1; D004338:Drug Combinations; D017671:Platinum Compounds; D043823:Taxoids; C080625:taxane