title: CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients.
abstract: OBJECTIVE
  Non-small cell lung cancer (NSCLC) occurs most frequently in individuals older than 60 years of age. Currently, no biological indicators associated with NSCLC in younger patients (30 to 60 y) have been identified. To explore epigenetic influences, promoter methylation of selected tumor suppressor genes was analyzed in early-stage NSCLC patients ranging in age from 30 to 87 years at diagnosis.
  
  
  METHODS
  The analysis was performed on formalin-fixed tumor tissue from 193 surgically treated NSCLC patients (127, older than 60 y; 66, 60 y and younger). Methylation was quantified in p16, MGMT, DAPK, RASSF1, CDH1, LET7-3-a, NORE1(RASSF5), and PTEN promoters by pyrosequencing. p16 protein expression was assessed by immunohistochemistry (IHC). Outcome, defined by time to recurrence and overall survival, was evaluated by Kaplan-Meier analysis.
  
  
  RESULTS
  Promoter methylation levels were generally higher in patients older than 60 years of age than in patients 60 years or younger at diagnosis. Of the genes tested, methylation levels of the p16 promoter showed age-related differences. Although p16 promoter methylation was significantly lower using cut-points of 50 years or younger and 40 years or younger (P=0.001 to 0.012, respectively), p16 protein expression increased with age. Patients 60 years or younger with p16 promoter hypermethylation had a significantly shortened time to recurrence (P=0.002) and a shortened survival time (P=0.011). No effect of p16 hypermethylation was seen in patients older than 60 years.
  
  
  CONCLUSIONS
  p16 promoter hypermethylation was associated with a worse outcome in patients with age at diagnosis of 60 years or younger, but was not associated with the outcome in the older than 60-year age group. Overall, these data support methylation-dependent and methylation-independent age-related regulation of p16 expression with differential effects on the outcome after surgical resection for early-stage NSCLC.
authors.affiliation: Department of Pathology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Dawn P
authors.initials: DP
authors.lastname: Bradly
authors.forename: Paolo
authors.initials: P
authors.lastname: Gattuso
authors.forename: Mark
authors.initials: M
authors.lastname: Pool
authors.forename: Sanjib
authors.initials: S
authors.lastname: Basu
authors.forename: Michael
authors.initials: M
authors.lastname: Liptay
authors.forename: Philip
authors.initials: P
authors.lastname: Bonomi
authors.forename: Lela
authors.initials: L
authors.lastname: Buckingham
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D019942:Genes, p16; D006801:Humans; D007087:Illinois / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011013:Pneumonectomy; D011379:Prognosis; D013902:Radiography, Thoracic; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16