title: CpG island hypermethylation of E-cadherin (CDH1) and integrin alpha4 is associated with recurrence of early stage esophageal squamous cell carcinoma.
abstract: The prognosis of esophageal squamous cell carcinoma (ESCC) patients remains very poor, which is partially due to a high rate of recurrence. This study was aimed at identifying a recurrence-associated epigenetic prognostic marker in patients with ESCC. We retrospectively analyzed the CpG island hypermethylation of the p16, Wif-1, sFRP1, integrin alpha4, CDH1, DAP kinase and RARbeta2 genes in 251 ESCCs. The methylation status was determined by methylation-specific PCR. Hypermethylation was detected in 52% for p16, 25% for RARbeta2, 43% for CDH1, 21% for integrin alpha4, 57% for sFRP1, 38% for DAP kinase and 35% for Wif-1. Recurrence was observed in 131 (52%) of the 251 cases. For stage I cancers, CDH1 methylation was associated with a high risk of recurrence (OR = 5.26, 95% CI = 1.48-18.67; p = 0.01) and a poor recurrence-free survival after surgery (HR = 3.13, 95% CI = 1.21-8.09; p = 0.02). The hazard of failure after recurrence was about 13.17 (95% CI = 2.46-70.41; p = 0.003) times higher in patients with Wif-1 methylation than in those without. For stage II cancers, integrin alpha4 methylation was associated with an increased risk of recurrence (OR = 3.03, 95% CI = 1.09-8.37; p = 0.03) and a poor recurrence-free survival (HR = 2.12, 95% CI = 1.13-3.98; p = 0.03). In conclusion, the present study suggests that hypermethylation of CDH1 and integrin alpha4 genes may be used as recurrence-associated prognostic indicators in stage I and stage II ESCCs, respectively.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Lee
authors.forename: Bo Bin
authors.initials: BB
authors.lastname: Lee
authors.forename: Joungho
authors.initials: J
authors.lastname: Han
authors.forename: Eun Yoon
authors.initials: EY
authors.lastname: Cho
authors.forename: Young Mog
authors.initials: YM
authors.lastname: Shim
authors.forename: Joobae
authors.initials: J
authors.lastname: Park
authors.forename: Duk-Hwan
authors.initials: DH
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D015703:Antigens, CD; D064007:Ataxia Telangiectasia Mutated Proteins; D015820:Cadherins / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012189:Retrospective Studies; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C485569:WIF1 protein, human; C082925:retinoic acid receptor beta; D039441:Integrin alpha4; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases