title: Unexpected close surgical margin in resected buccal cancer: very close margin and DAPK promoter hypermethylation predict poor clinical outcomes.
abstract: OBJECTIVE
  In resected buccal cancer patients, an unexpected close surgical margin has been observed to correlate with poor clinical outcomes. However, close surgical margin alone does not independently guide post-operative therapies, revealing a clinical debate. Hence, the present study intended to explore epigenetic-based bio-predictors for further stratifying this debating patient population.
  
  
  METHODS
  Between 2000 and 2008, we retrospectively recruited 44 resected buccal cancer patients with a close surgical margin of ≤5 mm. All patients had post-operative radiotherapy. Genomic DNA was extracted from tumor-enrich areas that contained cancer cells of >70%. Methylation-specific PCR was performed to detect promoter methylation of four tumor suppressor genes, including RASSF1A, DAPK, IRF8, and SFRP1. Post-irradiation locoregional control was defined as the primary end point.
  
  
  RESULTS
  There were 40 males and 4 females, with a median age of 53.5 years (range, 32-82 years). Multivariate analysis identified two independent predictors for locoregional recurrence: very close margin of ≤1 mm (HR: 4.96; 95% CI, 1.63-15.09; P=0.018) and promoter hypermethylation of DAPK (HR: 2.83; 95% CI, 1.05-7.63; P=0.042). The highest risk of locoregional recurrence was observed in patients with both of the two factors (HR, 8.05; 95% CI, 2.56-25.82; P=0.002) when compared with patients with none. Shorter disease-free survival, but not overall survival, was also observed.
  
  
  CONCLUSIONS
  More aggressive managements should be considered in resected buccal cancer patients with both very close margin and DAPK promoter hypermethylation rather than post-operative observation or radiotherapy alone.
authors.affiliation: Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC.
authors.forename: Hon-Yi
authors.initials: HY
authors.lastname: Lin
authors.forename: Tze-Ta
authors.initials: TT
authors.lastname: Huang
authors.forename: Moon-Sing
authors.initials: MS
authors.lastname: Lee
authors.forename: Shih-Kai
authors.initials: SK
authors.lastname: Hung
authors.forename: Ru-Inn
authors.initials: RI
authors.lastname: Lin
authors.forename: Chih-En
authors.initials: CE
authors.lastname: Tseng
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Chang
authors.forename: Wen-Yen
authors.initials: WY
authors.lastname: Chiou
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Hsu
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Hsu
authors.forename: Dai-Wei
authors.initials: DW
authors.lastname: Liu
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Su
authors.forename: Szu-Chi
authors.initials: SC
authors.lastname: Li
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002610:Cheek; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics / Q000601:surgery*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases