Abnormalities in maintenance of methylation and carcinogenesis.

• Project/Area Number: 11138265
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: National Cancer Center Resaerch Institute Carcinogenesis
• Principal Investigator: USHIJIMA Toshikazu National Cancer Center Res.Inst.Chief, 部長 (90232818)
• Co-Investigator(Kenkyū-buntansha): ASADA Kiyoshi National Cancer Center Res.Inst.Staff Scientist, 研究員 (50311410)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥5,000,000 (Direct Cost: ¥5,000,000); Fiscal Year 1999: ¥5,000,000 (Direct Cost: ¥5,000,000)
• Keywords: CpG island / DNA methylation / MS-RDA / Breast cancer / BRCA1 / G protein / Maintenance / Methylation instability

Research Abstract

The number and distribution of aberrant methylations in human breast cancers were investigated using a genome-wide scanning technique of aberrant methylations, methylation-sensitive-representational difference analysis (MS-RDA). MS-RDA of two human breast cancers revealed 25 hypermethylated DNA fragments and 22 hypomethylated DNA fragments. Prevalences of these aberrant methylations were examined using a total of 14 breast cancers. Five cancers showed high incidence of aberrant hyper- and hypomethylations, two showed high incidence of only aberrant hypomethylations, and the remaining seven showed limited number of aberrant methylations. These findings indicated that a subset of human breast cancers shows higher rate of occurrence of aberrant methylations than the others. To explore the underlying molecular abnormality for the "methylation instability", germline mutations of BRCA1 were analyzed in the 14 cases, but there was no correlation between the "methylation instability" and BRCA1 germline mutations. On the other hand, we identified a G-protein subunit and a cytoplasmic second messenger as genes that are hypermethylated and transcriptionally repressed in more than half of human breast cancers.

Research Products

• [Publications] Sugimura,T., and Ushijima,T.: "Genetic and epigenetic alterations in carcinogenesis."Mutation Research. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Honda,H., Ushijima,T. etl al.: "Acquired loss of p53 induced blastic transformation in p210^<bcr/abl>-expressing hematopoietic cells : a transgenic study for blast crisis of human CML."Blood. 95. 1144-1150 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ushijima,T. etl al.: "Acquired loss of p53 induced blastic transformation in p210^<bcr/abl>-expressing hematopoietic cells : a transgenic study for blast crisis of human CML."Cancer Res.. 60. 1092-1096 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Suzui,M., Ushijima,T. etl al.: "Frequent mutations in the rat b-catenin gene (Ctnnb1) of ulcerative colitis-associated colon cancer induced by 1-hydroxyanthraquinone and methylazoacetate."Mol.Carcinogenesis. 24. 232-237 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nagao,S., Ushijima,T. etl al.: "Closely linked polymorphic markers for determining the autosomal dominant allele (Cy) in rat polycystic kidney disease."Biochem.Genet.. 37. 227-235 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sugimura, T., and Ushijima, T.: "Genetic and epigenetic alterations in carcinogenesis."Mutat.Res.. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Honda, H., Ushijima, T., Wakazono, K., Oda, H., Tanaka, Y., Aizawa, S.-i., Ishikawa, T., Yazaki, Y.and Hirai, H.: "Acquired loss of p53 induced blastic transformation in p210^<bcr/abl>-expressing hematopoietic cells : a transgenic study for blast crisis of human CML."Blood. 95. 1144-1150 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ushijima, T., Yamamoto, M., Suzui, M., Kuramoto, T., Yoshida, Y., Nomoto, T., Tatematsu, M., Sugimura, T., and Nagao, M.: "Chromosomal mapping of genes controlling development, histological grade, depth of invasion and size of rat stomach carcinomas."Cancer Res. 60. 1092-1096 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Suzui, M., Ushijima, T., Dashwood, R.H., Yoshimi, N., Sugimura, T., Mori, H.and Nagao, M.: "Frequent mutations in the rat b-catenin gene (Ctnnb 1) of ulcerative colitis-associated colon cancer induced by 1-hydroxyanthraquinone and methylazoacetate."Mol.Carcinog.. 24. 232-237 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nagao, S., Ushijima, T., Kasahara, M., Yamaguchi, T., Kusaka, M., Matsuda, J., Nagao, M.and Takahashi, H.: "Closely linked polymorphic markers for determining the autosomal dominant allele (Cy) in rat polycystic kidney disease."Biochem.Genet.. 37. 227-235 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sugimura, T., and Ushijima, T.: "Genetic and epigenetic alterations in carcinogenesis"Mutation Research. (in press).
• [Publications] Honda, H., Ushijima, T.et al.: "Acquired loss of p53 induced blastic transformation in p210^<bcr/abl>-expressing hematopoietic cells : a transgenic study for blast crisis of human CML"Blood. 95. 1144-1150 (2000)
• [Publications] Ushijima, T.et al.: "Chromosomal mapping of genes controlling development, histological grade, depth of invasion and size of rat stomach carcinomas"Cancer Res.. 60. 1092-1096 (2000)
• [Publications] Suzui, M., Ushijima, T.et al.: "Frequent mutations in the rat b-catenin gene (Ctnnb1) of ulcerative colitis-associated colon cancer induced by 1-hydroxyanthraquinone and methylazoacetate"Mol. Carcinogenesis. 24. 232-237 (1999)
• [Publications] Nagao, S., Ushijima, T.atl al.: "Closely linked polymorphic markers for determining the autosomal dominant allele (Cy) in rat polycystic kidney disease"Biochem. Genet.. 37. 227-235 (1999)