臨床検査52巻6号

2008年06月発行

記事購入ページに移動

今月の主題 エピジェネティクスと臨床検査 総論

癌とエピジェネティクス―Cancer epigenetics

著者： 牛島俊和¹

所属機関： ¹国立がんセンター研究所発がん研究部

ページ範囲：P.629 - P.635

　癌には固有のDNAメチル化異常がある．特にプロモーター領域CpGアイランドのDNAメチル化異常は，癌抑制遺伝子不活化の原因(ドライバー)となりうる．癌化の随伴現象のDNAメチル化異常(パッセンジャー)も多数認められるが，診断的に有用な場合がある．癌細胞特異的なDNAメチル化異常を検出する癌の存在診断，手術材料を用いる薬剤反応性や予後の診断，一見正常に見える組織でのDNAメチル化異常を用いる癌のリスク診断は，実用化の時代を迎えつつある．

参考文献

１) 牛島俊和，大河内江里子，山下聡：癌におけるDNAメチル化異常　発癌における意義と臨床への応用．細胞工学　25：1058-1063，2006

２) Jones PA, Baylin SB：The epigenomics of cancer. Cell　128：683-692, 2007

３) Riggs AD, Xiong Z：Methylation and epigenetic fidelity. Proc Natl Acad Sci USA　101：4-5, 2004

４) 牛島俊和：重要性が増すエピジェネティクスと進化する解析技術．バイオテクノロジージャーナル　7：406-409，2007

５) Kaneda A, Tsukamoto T, Takamura-Enya T, et al：Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation. Cancer Sci　95：58-64, 2004

６) Gaudet F, Hodgson JG, Eden A, et al：Induction of tumors in mice by genomic hypomethylation. Science　300：489-492, 2003

７) Yamada Y, Jackson-Grusby L, Linhart H, et al：Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA　102：13580-13585, 2005

８) Cui H, Onyango P, Brandenburg S, et al：Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res　62：6442-6446, 2002

９) Ushijima T, Sasako M：Focus on gastric cancer. Cancer Cell　5：121-125, 2004

10) Li B, Carey M, Workman JL：The role of chromatin during transcription. Cell　128：707-719, 2007

11) Lin JC, Jeong S, Liang G, et al：Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell　12：432-444, 2007

12) Ushijima T：Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer　5：223-231, 2005

13) Weber M, Davies JJ, Wittig D, et al：Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet　37：853-862, 2005

14) Yamashita S, Tsujino Y, Moriguchi K, et al：Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci　97：64-71, 2006

15) Miyamoto K, Ushijima T：Diagnostic and therapeutic applications of epigenetics. Jpn J Clin Oncol　35：293-301, 2005

16) 牛島俊和：エピジェネティクスの診断への応用と癌細胞の鋭敏な検出．実験医学　25：2670-2677，2007

17) Toyota M, Ahuja N, Ohe-Toyota M, et al：CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA　96：8681-8686, 1999

18) Abe M, Ohira M, Kaneda A, et al：CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res　65：828-834, 2005

19) Weisenberger DJ, Siegmund KD, Campan M, et al：CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet　38：787-793, 2006

20) Abe M, Westermann F, Nakagawara A, et al：Marked and independent prognostic significance of the CpG island methylator phenotype in neuroblastomas. Cancer Lett　247：253-258, 2007

21) Enomoto S, Maekita T, Tsukamoto T, et al：Lack of association between CpG island methylator phenotype in human gastric cancers and methylation in their background non-cancerous gastric mucosae. Cancer Sci　98：1853-1861, 2007

22) Kaneda A, Kaminishi M, Yanagihara K, et al：Identification of silencing of nine genes in human gastric cancers. Cancer Res　62：6645-6650, 2002

23) Miyamoto K, Fukutomi T, Akashi-Tanaka S, et al：Identification of 20 genes aberrantly methylated in human breast cancers. Int J Cancer　116：407-414, 2005

24) An C, Choi IS, Yao JC, et al：Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clin Cancer Res　11：656-663, 2005

25) Etoh T, Kanai Y, Ushijima S, et al：Increased DNA methyltransferase 1(DNMT1)protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol　164：689-699, 2004

26) Ushijima T：Epigenetic field for cancerization. J Biochem Mol Biol　40：142-150, 2007

27) Maekita T, Nakazawa K, Mihara M, et al：High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res　12：989-995, 2006

28) Nakajima T, Maekita T, Oda I, et al：Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol Biomarkers Prev　15：2317-2321, 2006

29) Chen WD, Han ZJ, Skoletsky J, et al：Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst　97：1124-1132, 2005

30) Sato N, Fukushima N, Maitra A, et al：Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res　63：3735-3742, 2003

31) Das PM, Singal R：DNA methylation and cancer. J Clin Oncol　22：4632-4642, 2004

32) Esteller M, Herman JG：Generating mutations but providing chemosensitivity：the role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene　23：1-8, 2004

33) Shen L, Kondo Y, Rosner GL, et al：MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst　97：1330-1338, 2005

34) Yan PS, Venkataramu C, Ibrahim A, et al：Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin Cancer Res　12：6626-6636, 2006

35) Arai E, Kanai Y, Ushijima S, et al：Regional DNA hypermethylation and DNA methyltransferase(DNMT)1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues. Int J Cancer　119：288-296, 2006

36) Kaminskas E, Farrell A, Abraham S, et al：Approval summary：azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res　11：3604-3608, 2005