CpG island hypermethylation of E-cadherin (CDH1) and integrin alpha4 is associated with recurrence of early stage esophageal squamous cell carcinoma.
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.
Lee
Eun Ju
EJ
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
Lee
Bo Bin
BB
Han
Joungho
J
Cho
Eun Yoon
EY
Shim
Young Mog
YM
Park
Joobae
J
Kim
Duk-Hwan
DH
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
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