title: A prospective study of tumor suppressor gene methylation as a prognostic biomarker in surgically resected stage I to IIIA non-small-cell lung cancers.
abstract: BACKGROUND
  While retrospective analyses support an association between early tumor recurrence and tumor suppressor gene promoter methylation in early-stage non-small-cell lung cancers (NSCLCs), few studies have investigated this question prospectively.
  
  
  METHODS
  Primary tumor tissue from patients with resected pathologic stage I to IIIA NSCLCs was collected at the time of surgery and analyzed for promoter methylation via methylation-specific reverse transcriptase polymerase chain reaction (MethyLight). The primary objective was to determine an association between promoter methylation of 10 individual tumor suppressor genes (CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, SOCS3, and ADAMTS8) and recurrence-free survival (RFS), with the secondary objectives of determining association with overall survival (OS), and relation to clinical or pathologic features.
  
  
  RESULTS
  A total of 107 patients had sufficient tumor tissue for successful promoter methylation analysis. Majority of patients were former/current smokers (88%) with lung adenocarcinoma (78%) and pathologic stage I disease (62%). Median follow-up was 4 years. When controlled for pathologic stage, promoter methylation of the individual genes CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, and ADAMTS8 was not associated with RFS. Promoter methylation of the same genes was not associated with OS except for DAPK1 which was associated with improved OS (p = 0.03). The total number of genes with methylated promoters did not correlate with RFS (p = 0.89) or OS (p = 0.55).
  
  
  CONCLUSIONS
  Contrary to data established by previous retrospective series, tumor suppressor gene promoter methylation (CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, and ADAMTS8) was not prognostic for early tumor recurrence in this prospective study of resected NSCLCs.
authors.affiliation: *Memorial Sloan Kettering Cancer Center, New York, NY; †Tokyo Medical and Dental University, Tokyo, Japan; and ‡Massachusetts General Hospital Cancer Center, Boston, MA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sugita
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.forename: Marjorie
authors.initials: M
authors.lastname: Zauderer
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Valerie W
authors.initials: VW
authors.lastname: Rusch
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011013:Pneumonectomy / Q000379:methods*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D004273:DNA, Neoplasm