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

• Published in: Oncogene Vol. 19; no. 32; pp. 3642 - 3646
• Main Authors: TSUCHIYA, T, TAMURA, G, WILSON, K. T, JAMES, S. P, JING YIN, FLEISHER, A. S, TONGTONG ZOU, SILVERBERG, S. G, DEHE KONG, MELTZER, S. J, SATO, K, ENDOH, Y, SAKATA, K, ZHE JIN, MOTOYAMA, T, USUBA, O, KIMURA, W, NISHIZUKA, S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 27.07.2000; Nature Publishing Group
• Subjects: Adenomatous polyposis coli; Adolescent; Base Sequence; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colorectal cancer; Colorectal carcinoma; CpG islands; DNA Methylation; DNA, Neoplasm - metabolism; Epigenetics; Exons; Female; Fundamental and applied biological sciences. Psychology; Gastric cancer; Gastric Mucosa - metabolism; Gene Expression; Genes, APC; Genetic disorders; Humans; Medicine; Molecular and cellular biology; Molecular Sequence Data; Mutation; Phenotypes; Polyposis coli; Promoter Regions, Genetic; Promoters; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms - genetics; Tumor cell lines; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; California; United States > US; Maryland; Japan; Baltimore Maryland; Human; Stomach; Nucleotide sequence; Transcription promoter; Familial adenomatous polyposis coli; Gene expression; Carcinogenesis; Genetic disease; Cell line; Messenger RNA; Rectum; Digestive diseases; Tumor; Colon; Methylation; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203704

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. 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 some gastric cancers. APC 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 evaluated 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.