Analysis and risk assessment of diffuse gastric cancer based on inflammation-induced epigenetic alterations

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390210
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: SHINOMURA Yasuhisa Sapporo Medical University, 医学部, 教授 (90162619)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Hiroyuki 札幌医科大学, 医学部, 講師 (40332910) ; SUZUKI Hiromu 札幌医科大学, 医学部, 助教 (20381254)
• Project Period (FY): 2008 – 2010
• Keywords: 遺伝子診断 / 遺伝子変異 / メチル化 / 前癌病変 / H.pylori

Research Abstract

In the current study, we have analyzed for aberrant DNA methylation which is associated with Helicobacter pylori (H.pylori) induced gastric carcinogenesis. We have shown evidences that both CpG island hypermethylation of cancer-related genes and global hypomethylation occurs in premalignant lesions of diffuse gastric cancer. In addition, through genome-wide screening, we have identified aberrant DNA methylation of novel gastric cancer-related genes and microRNAs. Functional analysis revealed that these are candidate gastric cancer suppressor genes, and DNA methylation analysis in clinical samples suggested that these could be useful risk markers of gastric cancer.

Research Products

• [Journal Article] Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer. (2011)
  • Author(s): Yamamoto E, Suzuki H, Takamaru H, Yamamoto H, Toyota M, Shinomura Y.
  • Journal Title: Digestion 83 Pages: 241-249
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis. (2011)
  • Author(s): Hizaki K, Yamamoto H, Taniguchi H, Adachi Y, Nakazawa M, Tanuma T, Kato N, Sukawa Y, Sanchez JV, Suzuki H, Sasaki S, Imai K, Shinomura Y.
  • Journal Title: Mod Pathol
  • Peer Reviewed
• [Journal Article] A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. (2010)
  • Author(s): Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernandez AF, Davalos V, Villanueva A, Montoya G, Yamamoto H, Schwartz S, Jr., Esteller M.
  • Journal Title: Cancer Cell 18 Pages: 303-315
  • Peer Reviewed
• [Journal Article] A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors. (2010)
  • Author(s): Igarashi S, Suzuki H, Niinuma T, Shimizu H, Nojima M, Iwaki H, Nobuoka T, Nishida T, Miyazaki Y, Takamaru H, Yamamoto E, Yamamoto H, Tokino T, Hasegawa T, Hirata K, Imai K, Toyota M, Shinomura Y.
  • Journal Title: Clin Cancer Res 16 Pages: 5114-5123
  • Peer Reviewed
• [Journal Article] IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. (2010)
  • Author(s): Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto E, Kai M, Akashi H, Watanabe Y, Yamamoto H, Sasaki Y, Itoh F, Imai K, Sugai T, Shen L, Issa JP, Shinomura Y, Tokino T, Toyota M.
  • Journal Title: Carcinogenesis 31 Pages: 342-349
  • Peer Reviewed
• [Journal Article] Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. (2010)
  • Author(s): Suzuki H, Yamamoto E, Nojima M, Kai M, Yamano HO, Yoshikawa K, Kimura T, Kudo T, Harada E, Sugai T, Takamaru H, Niinuma T, Maruyama R, Yamamoto H, Tokino T, Imai K, Toyota M, Shinomura Y.
  • Journal Title: Carcinogenesis 31 Pages: 2066-2073
  • Peer Reviewed
• [Journal Article] A candidate targeting molecule of insulin-like growth factor-I receptor for gastrointestinal cancers. (2010)
  • Author(s): Adachi Y, Yamamoto H, Ohashi H, Endo T, Carbone DP, Imai K, Shinomura Y.
  • Journal Title: World J Gastroenterol 16 Pages: 5779-5789
  • Peer Reviewed
• [Journal Article] Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers. (2010)
  • Author(s): Wang Y, Adachi Y, Imsumran A, Yamamoto H, Piao W, Li H, Ii M, Arimura Y, Park MY, Kim D, Lee CT, Carbone DP, Imai K, Shinomura Y.
  • Journal Title: J Gastroenterol 45 Pages: 159-170
  • Peer Reviewed
• [Journal Article] A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. (2009)
  • Author(s): Melo SA, Ropero S, Moutinho C, Aaltonen LA, Yamamoto H, Calin GA, Rossi S, Fernandez AF, Carneiro F, Oliveira C, Ferreira B, Liu CG, Villanueva A, Capella G, Schwartz S, Jr., Shiekhattar R, Esteller M.
  • Journal Title: Nat Genet 41 Pages: 365-470
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. (2009)
  • Author(s): Taniguchi H, Fernandez AF, Setien F, Ropero S, Ballestar E, Villanueva A, Yamamoto H, Imai K, Shinomura Y, Esteller M.
  • Journal Title: Cancer Res 69 Pages: 8447-8454
  • Peer Reviewed
• [Journal Article] Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen. (2009)
  • Author(s): Yamaoka S, Yamamoto H, Nosho K, Taniguchi H, Adachi Y, Sasaki S, Arimura Y, Imai K, Shinomura Y.
  • Journal Title: World J Gastroenterol 15 Pages: 5579-5585
  • Peer Reviewed
• [Journal Article] Overexpression of beta3/gamma2 chains of laminin-5 and MMP7 in biliary cancer. (2009)
  • Author(s): Oka T, Yamamoto H, Sasaki S, Ii M, Hizaki K, Taniguchi H, Adachi Y, Imai K, Shinomura Y.
  • Journal Title: World J Gastroenterol 15 Pages: 3865-3873
  • Peer Reviewed
• [Journal Article] Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. (2009)
  • Author(s): Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki Y, Isobe M, Fujimiya M, Imai K, Shinomura Y.
  • Journal Title: J Pathol 218 Pages: 350-359
  • Peer Reviewed
• [Journal Article] Cancer epigenomics : implications of DNA methylation in personalized cancer therapy. (2009)
  • Author(s): Toyota M, Suzuki H, Yamashita T, Hirata K, Imai K, Tokino T, Shinomura Y.
  • Journal Title: Cancer Sci 100 Pages: 787-791
  • Peer Reviewed
• [Journal Article] Genomic screening for genes silenced by DNA methylation revealed an association between RASD1 inactivation and dexamethasone resistance in multiple myeloma. (2009)
  • Author(s): Nojima M, Maruyama R, Yasui H, Suzuki H, Maruyama Y, Tarasawa I, Sasaki Y, Asaoku H, Sakai H, Hayashi T, Mori M, Imai K, Tokino T, Ishida T, Toyota M, Shinomura Y.
  • Journal Title: Clin Cancer Res 15 Pages: 4356-4364
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. (2009)
  • Author(s): Asano K, Matsushita T, Umeno J, Hosono N, Takahashi A, Kawaguchi T, Matsumoto T, Matsui T, Kakuta Y, Kinouchi Y, Shimosegawa T, Hosokawa M, Arimura Y, Shinomura Y, Kiyohara Y, Tsunoda T, Kamatani N, Iida M, Nakamura Y, Kubo M.
  • Journal Title: Nat Genet 41 Pages: 1325-1329
  • Peer Reviewed
• [Journal Article] LINE-1 hypomethylation is associated with increased CpG island methylation in Helicobacter pylori-related enlarged-fold gastritis. (2008)
  • Author(s): Yamamoto E, Toyota M, Suzuki H, Kondo Y, Sanomura T, Murayama Y, Ohe-Toyota M, Maruyama R, Nojima M, Ashida M, Fujii K, Sasaki Y, Hayashi N, Mori M, Imai K, Tokino T, Shinomura Y.
  • Journal Title: Cancer Epidemiol Biomarkers Prev 17 Pages: 2555-2564
  • Peer Reviewed
• [Journal Article] Correlation of laterally spreading type and JC virus with methylator phenotype status in colorectal adenoma. (2008)
  • Author(s): Nosho K, Yamamoto H, Takahashi T, Mikami M, Hizaki K, Maehata T, Taniguchi H, Yamaoka S, Adachi Y, Itoh F, Imai K, Shinomura Y.
  • Journal Title: Hum Pathol 39 Pages: 767-775
  • Peer Reviewed
• [Journal Article] Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer. (2008)
  • Author(s): Maruyama R, Akino K, Toyota M, Suzuki H, Imai T, Ohe-Toyota M, Yamamoto E, Nojima M, Fujikane T, Sasaki Y, Yamashita T, Watanabe Y, Hiratsuka H, Hirata K, Itoh F, Imai K, Shinomura Y, Tokino T.
  • Journal Title: Carcinogenesis 29 Pages: 1312-1318
  • Peer Reviewed
• [Journal Article] Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. (2008)
  • Author(s): Oki M, Yamamoto H, Taniguchi H, Adachi Y, Imai K, Shinomura Y.
  • Journal Title: World J Gastroenterol 14 Pages: 5650-5656
  • Peer Reviewed
• [Journal Article] DNA methylation and cancer pathways in gastrointestinal tumors. (2008)
  • Author(s): Suzuki H, Tokino T, Shinomura Y, Imai K, Toyota M.
  • Journal Title: Pharmacogenomics 9 Pages: 1917-1928
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. (2008)
  • Author(s): Takagi H, Sasaki S, Suzuki H, Toyota M, Maruyama R, Nojima M, Yamamoto H, Omata M, Tokino T, Imai K, Shinomura Y.
  • Journal Title: J Gastroenterol 43 Pages: 378-389
  • Peer Reviewed
• [Journal Article] Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. (2008)
  • Author(s): Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y, Tokino T.
  • Journal Title: Cancer Res 68 Pages: 4123-4132
  • Peer Reviewed
• [Journal Article] A requirement for DICER to maintain full promoter CpG island hypermethylation in human cancer cells. (2008)
  • Author(s): Ting AH, Suzuki H, Cope L, Schuebel KE, Lee BH, Toyota M, Imai K, Shinomura Y, Tokino T, Baylin SB.
  • Journal Title: Cancer Res 68 Pages: 2570-2575
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma. (2008)
  • Author(s): Imai T, Toyota M, Suzuki H, Akino K, Ogi K, Sogabe Y, Kashima L, Maruyama R, Nojima M, Mita H, Sasaki Y, Itoh F, Imai K, Shinomura Y, Hiratsuka H, Tokino T.
  • Journal Title: Cancer Sci 99 Pages: 958-966
  • Peer Reviewed
• [Presentation] 消化管間質腫瘍におけるLINE-1低メチル化と悪性度との相関 (2010)
  • Author(s): 山本英一郎, 鈴木拓, 新沼猛, 五十嵐伸一, 山本博幸, 豊田実, 篠村恭久
  • Organizer: 第21回日本消化器癌発生学会総会
  • Place of Presentation: 軽井沢
  • Year and Date: 20101118-20101119
• [Presentation] GISTにおけるエピジェネティックな異常とその臨床的意義 (2010)
  • Author(s): 鈴木拓, 新沼猛, 篠村恭久
  • Organizer: 第18回日本消化器病関連学会週間
  • Place of Presentation: 横浜
  • Year and Date: 20101013-20101016
• [Presentation] 未分化型胃癌におけるDNAメチル化異常の解明 (2010)
  • Author(s): 高丸博之, 鈴木拓, 山本英一郎, 新沼猛, 田沼徳真, 安井寛, 甲斐正広, 山本博幸, 豊田実, 篠村恭久
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20100922-20100924
• [Presentation] GISTにおけるHNE-1低メチル化と悪性度との相関 (2010)
  • Author(s): 新沼猛, 鈴木拓, 野島正寛, 五十嵐伸一, 山本英一郎, 高丸博之, 田沼徳真, 山本博幸, 時野隆至, 今井浩三, 豊田実, 篠村恭久
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20100922-20100924
• [Presentation] CIMP大腸癌の起源 (2010)
  • Author(s): 山本英一郎, 鈴木拓, 山野泰穂, 神前正幸, 甲斐正広, 菅井有, 時野隆至, 今井浩三, 篠村恭久, 豊田実
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20100922-20100924
• [Presentation] 次世代シークエンサーを用いた遺伝子転写開始点予測とエピゲノム解析への応用 (2010)
  • Author(s): 豊田実, 鈴木拓, 野島正寛, 佐々木泰史, 篠村恭久, 時野隆至, 今井浩三
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20100922-20100924
• [Presentation] microRNAプロセシングに関わるTARBP2遺伝子の消化管癌における変異及び機能解析 (2010)
  • Author(s): 宮本伸樹, 山本博幸, 宮本千絵, 谷口博昭, 足立靖, 日崎恵一, 井伊正則, 田沼徳真, 須河恭敬, 佐々木茂, 有村佳昭, 篠村恭久
  • Organizer: 第6回日本消化管学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 20100219-20100220
• [Presentation] 胃癌におけるmicroRNA34b/cのエピジェネティックな不活化 (2010)
  • Author(s): 鈴木拓, 山本英一郎, 高丸博之, 五十嵐伸一, 野島正寛, 山本博幸, 豊田実, 今井浩三, 篠村恭久
  • Organizer: 第6回日本消化管学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2010-02-19
• [Presentation] 多発胃癌背景胃粘膜における異常メチル化 (2009)
  • Author(s): 山本英一郎, 豊田実, 鈴木拓, 山本博幸, 山野泰穂, 菅井有, 今井浩三, 篠村恭久
  • Organizer: 第20回日本消化器癌発生学会総会
  • Place of Presentation: 広島
  • Year and Date: 20091126-20091127
• [Presentation] 大腸癌におけるIGFBP7のメチル化とCIMPとの相関 (2009)
  • Author(s): 鈴木拓, 五十嵐伸一, 高丸博之, 新沼猛, 山本英一郎, 野島正寛, 山本博幸, 豊田実, 今井浩三, 篠村恭久
  • Organizer: 第20回日本消化器癌発生学会総会
  • Place of Presentation: 広島
  • Year and Date: 20091126-20091127
• [Presentation] 胃癌の進展におけるラミニンβ3とγ2の共発現の役割 (2009)
  • Author(s): 井伊正則, 山本博幸, 足立靖, 谷口博昭, 日崎恵一, 大橋広和, 田沼徳真, 國本浩明, 阿久津典之, 佐々木茂, 有村佳昭, 今井浩三, 篠村恭久
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] 大腸癌においてエピジェネティックに不活化したmicroRNAの網羅的解析 (2009)
  • Author(s): 鈴木拓, 五十嵐伸一, 高丸博之, 新沼猛, 山本博幸, 時野隆至, 今井浩三, 豊田実, 篠村恭久
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] 新規エピゲノム解析法の開発と消化器癌発生の分子機構 (2009)
  • Author(s): 豊田実, 鈴木拓, 山本英一郎, 山野泰穂, 篠村恭久
  • Organizer: 第5回日本消化管学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20090212-20090213
• [Presentation] 皺壁肥大型胃炎におけるゲノムワイドな低メチル化とCpGアイランド高メチル化の関連 (2008)
  • Author(s): 山本英一郎, 豊田実, 鈴木拓, 野島正寛, 丸山玲緒, 五十嵐伸一, 時野隆至, 今井浩三, 篠村恭久
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20081028-20081030
• [Presentation] JCウイルスT抗原発現陽性胃癌のジェネティックおよびエピジェネティックな異常 (2008)
  • Author(s): 山本博幸, 山岡聡, 宮本千絵, 井伊正則, 日崎恵一, 田沼徳真, 宮本伸樹, 奥田博介, 足立靖, 佐々木茂, 有村佳昭, 今井浩三, 篠村恭久
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20081028-20081030
• [Presentation] IGF-I受容体標的治療はマトリライシンの抑制を介してヒト消化器癌の浸潤を抑制する (2008)
  • Author(s): 足立靖, 山本博幸, 井伊正則, 有村佳昭, 遠藤高夫, 加藤康夫, 今井浩三, 篠村恭久
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20081028-20081030
• [Presentation] ゲノムワイドな低メチル化を指標とした胃癌の診断と発癌リスク予測への応用 (2008)
  • Author(s): 山本英一郎, 豊田実, 篠村恭久
  • Organizer: 第16回日本消化器関連学会週間
  • Place of Presentation: 東京
  • Year and Date: 20081001-20081004
• [Book] バイサルファイトPCR法(新遺伝子工学ハンドブック)(村松正實,山本雅,岡崎康司編)改訂第5版 東京 (2010)
  • Author(s): 鈴木拓, 豊田実
  • Total Pages: 115-121
  • Publisher: 羊土社
• [Book] Inflammation-related aberrant patterns of DNA methylation : detection and role in epigenetic deregulation of cancer cell transcriptome. Inflammation and Cancer. Methods and Protocols : Volume 2 : Molecular Analysis and Pathways. Methods in Molecular Biology Edited by Serguei V. New York, USA. 512 (2009)
  • Author(s): Suzuki H, Toyota M, Kondo Y, Shinomura Y.
  • Total Pages: 55-69
  • Publisher: Kozlov. Humana Press