Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

Takashi Tsuchiya, Gen Tamura, Kiyoshi Sato, Yasushi Endoh, Ken Sakata, Zhe Jin, Teiichi Motoyama, Osamu Usuba, Wataru Kimura, Satoshi Nishizuka, Keith T. Wilson, Stephen P. James, Jing Yin, A. Steven Fleisher, Tongtong Zou, Steven G. Silverberg, Dehe Kong, Stephen J. Meltzer

Research output: Contribution to journalArticlepeer-review

Abstract

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal ranters. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least same gastric cancers. A PC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B respectively. We calculated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%,) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

Original languageEnglish (US)
Pages (from-to)3642-3646
Number of pages5
JournalOncogene
Volume19
Issue number32
DOIs
StatePublished - Jul 27 2000
Externally publishedYes

Keywords

  • APC
  • Gastric cancer
  • Hypermethylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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