title: Clinical correlates of promoter hypermethylation of four target genes in head and neck cancer: a cooperative group correlative study.
abstract: OBJECTIVE
  Promoter hypermethylation is a well-documented mechanism for tumor-specific alteration of suppressor gene activity in human malignancy including head and neck cancer (HNC). The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome. In this study we examined methylation of DCC, KIF1A, EDNRB, and p16(INK4a) in a large cohort of HNC patients from Eastern Cooperative Group (ECOG) 4393/Radiation Therapy Oncology Group (RTOG) 9614 to identify clinical correlates of methylation of these genes.
  
  
  METHODS
  Methylation was assessed by quantitative methylation-specific PCR in DNA from tumor specimens and was considered as a continuous and a binary variable. Clinical data including demographics, stage, risk factor exposure, treatment, and outcome were collected by ECOG and RTOG. Methylation status was also correlated with mutation of TP53 (previously reported) and human papilloma virus status.
  
  
  RESULTS
  Methylation results were available for 368 cases, 353 of which also have p53 mutation status. At least one methylation event was present in all tumors. In multivariate analysis of the entire cohort, methylation of p16 was associated with decreased survival (HR = 1.008; P = 0.045). However, in tumors with disruptive TP53 mutation (poor prognostic group), the additional presence of methylation of p16 was protective (P = 0.019 considering p16 methylation as a continuous variable).
  
  
  CONCLUSIONS
  Methylation of tumor-related genes contributes to the biological behavior of HNC and influences overall survival in conjunction with other known prognostic molecular events.
authors: Departments of Otolaryngology-Head, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
authors: Jong-Lyel
authors: JL
authors: Roh
authors: Xin Victoria
authors: XV
authors: Wang
authors: Judith
authors: J
authors: Manola
authors: David
authors: D
authors: Sidransky
authors: Arlene A
authors: AA
authors: Forastiere
authors: Wayne M
authors: WM
authors: Koch
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D000075389:DCC Receptor; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D016547:Kinesins / Q000235:genetics; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D044023:Receptor, Endothelin B / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D000075389:DCC Receptor; C501909:DCC protein, human; C094065:KIF1A protein, human; D044023:Receptor, Endothelin B; D011956:Receptors, Cell Surface; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016547:Kinesins