Field defect of methylation changes in esophageal adenocarcinomas in patients from Japan and the United States

Motomi Nasu, Michael K. Gibson, Malcolm Brock, Hajime Orita, Li Xu, James Herman, Arlene Forastiere, Yoshiaki Kajiyama, Masahiko Tsurumaru

Research output: Contribution to journalArticlepeer-review


Purpose: Esophageal mucosae that reside next to gross cancer are often without histological premalignant changes. We hypothesized that DNA hypermethylation could be detected in "normal" tissues adjacent to esophageal adenocarcinomas (EAC). Design: A cohort of patients from Japan (J, n=14) and the United States (U.S., n=56) with locally advanced EAC were evaluated for methylation status. Esophagectomy specimens provided a source of paired normal and tumor tissues. After DNA extraction, methylation specific PCR was used to evaluate the promoters of APC, p16 and MGMT in all samples. Methylation frequency was calculated for each gene and expressed as a percentage of total. Results: Age, gender, pathologic stage and epigenetic analyses of primary tumors were similar in each cohort. Methylation frequency of tumors was: APC (66% U.S.; 70% J). p16 (39% U.S.; 20% J). MGMT (63% U.S.; 75% J). In adjacent histologically normal esophageal mucosae, the percentage of patients with methylation at 0, 1, 2 or 3 genes was 79%, 14%, 0%, 7% for the Japanese group and 47%, 34%, 7% and 2% for the U.S. group. In both cohorts, the majority of the normal samples had no methylation changes. In over half of the total cohort, however, there was at least one gene in the adjacent histologically normal tissue positive for DNA hypermethylation. Very few samples in either group, however, had more than one gene methylated in histologically "normal" esophageal mucosae. In general, the same methylation pattern present in the normal tissue persisted in the primary malignancy. Conclusion: Histologically normal esophageal mucosae frequently show at least one hypermethylated gene in a multiple gene panel. These data suggest that for patients with EAC, regardless of nationality, there is a field defect of promoter hypermethylation changes in adjacent esophageal mucosae. These events reflect those of the primary malignancy, and are probably early and cumulative during carcinogenesis.

Original languageEnglish (US)
Pages (from-to)105-108
Number of pages4
JournalCancer Therapy
Issue numberISSUE A
StatePublished - 2010


  • Esophageal Cancer
  • Gene Methylation
  • Pre-malignancy

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Cancer Research


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