Genome-wide Analysis of Hypermethylated Genes in Colon Cancer with Liver Metastasis

• Project/Area Number: 19591607
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: SANO Tsuyoshi Aichi Cancer Center Research Institute, 分子腫瘍学部, 研究員 (60303632)
• Co-Investigator(Kenkyū-buntansha): KONDO Yutaka 愛知県がんセンター(研究所), 分子腫瘍学部, 室長 (00419897)
• Co-Investigator(Renkei-kenkyūsha): SHIMIZU Yasuhiro 愛知県がんセンター(研究所), 分子腫瘍学部, 研究員 (40470166)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2007: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 大腸がん / DNAメチル化 / マイクロアレイ / 肝転移 / エピジェネティクス

Research Abstract

DNAメチル化は、遺伝子の発現抑制を介してがんの発生・進展に関与している。本研究は大腸がんの肝転移に関わる遺伝子のうち、特にDNAメチル化により制御される遺伝子の網羅的解析を行ない、大腸がんの肝転移に関与する遺伝子の同定と、新しい肝転移診断マーカーの開発を目指した。まずDNAメチル化標的遺伝子の網羅的解析法として、(Methylated CpG island Amplification-マイクロアレー法 ; MCAM法)を用いて、大腸がん原発巣(CRC)および転移巣(meta)のDNAメチル化標的遺伝子のプロファイリングを行った。大腸がんはMCAM法によりDNAメチル化が腫瘍内に集積するCpG island methylator phenotype (CIMP)症例とCIMP陰性症例に分類可能であった CIMP陽性症例と陰性症例では肝転移の頻度には有意な差は認めなかった。CIMP陽性・陰性症例で正常粘膜のDNAメチル化を、大腸の部位別に詳細に解析し、大腸がんの発がん過程におけるDNAメチル化の蓄積は大腸の部位によって異なる様相を呈することを見出した。すなわち近位部大腸に関与が深いCIMP陽性症例に対し、遠位部大腸ではDNAメチル化蓄積は年齢と強い相関を認め、その蓄積が発がんに関与していると考えた。次に9例の手術症例で同一患者のCRCとmetaの組織からDNAを抽出した。これらの症例はCRCではCIMP陽性例2例 CIMP陰性例7例であった。全症例の平均では、CRC特異的、meta特異的、両者共通メチル化遺伝子は568遺伝子、579遺伝子、515遺伝子であった。これらの遺伝子のうち複数症例で共通してメチル化した遺伝子を選択し、研究期間内に蓄積した症例を用いて肝転移巣に特異的なメチル化標的遺伝子の解析を行なっている。以上の結果と臨床病理学的背景との相関から、大腸がんの肝転移に関与する遺伝子の同定と、新しい肝転移診断マーカーの開発に結びつけることが期待できる。

Research Products

• [Journal Article] Validity of observation interval for synchronous hepatic metastases of colorectal cancer : changes in hepatic and extrahepatic metastatic foci. (2008)
  • Author(s): Shimizu Y, Yasui K, Sano T, Hirai T, Kanemitsu Y, Komori K, Kato T
  • Journal Title: Langenbeck's Arch Surg. 393 Pages: 181-184
• [Journal Article] Reconstruction of hepatic venous tributaries using a Y-shaped left portal vein graft harvested from a resected left liver (2008)
  • Author(s): Sano T, Shimada K, Nara S, Sakamoto Y, Kosuge T
  • Journal Title: Hepatogastroenterology 55 Pages: 228-230
• [Journal Article] Downregulation of Histone H3 Lysine 9 Methyltransferase G9a Induces Centrosome Disruption and Chromosome Instability in Cancer Cells (2008)
  • Author(s): Kondo Y, Shen L, Ahmed S, Boumber Y, Sekido Y, Haddad BR, Issa JP
  • Journal Title: PloS One 3
• [Journal Article] Gene silencing in cancer by histone H3 lysine 27 tri-methylation independent of promoter DNA methylation (2008)
  • Author(s): Kondo Y, Shen L, Cheng A, Ahmed S, Boumber Y, Charo C, Yamochi T, Urano T, Furukawa K, Kwabi-Addo B, Gold D, Sekido Y, Huang T, Issa JP
  • Journal Title: Nat Genet. 40 Pages: 741-750
• [Journal Article] An Sp1/Sp3 binding polymorphism confers methylation protection (2008)
  • Author(s): BoumberYA, Kondo Y, Chen X, Shen L, Guo Y, Tellez C, Estecio MR, Ahmed S, Issa JP
  • Journal Title: PLoS Genet. 4
• [Journal Article] Variable DNA Methylation Patterns Associated with Progression of Disease in Hepatocellular Carcinomas (2008)
  • Author(s): Gao W, Kondo Y, Shen L, Shimizu Y, Sano T, Yamao K, Natsume A, Goto Y, Ito M, Murakami H, Osada H, Zhang J, Issa JPJ, Sekido Y
  • Journal Title: Carcinogenesis 29 Pages: 1901-10
• [Journal Article] Variable DNA methylation patterns associated with progression of disease in hepatocellular carcino (2008)
  • Author(s): Gao W
  • Journal Title: Carcinogenesis 29 Pages: 2139-46
  • Peer Reviewed
• [Journal Article] Validity of observation interval for synchronous hepatic metastases of colorectal cancer : changes ir (2008)
  • Author(s): Shimizu Y
  • Journal Title: langenbecks Arch Surg. 393 Pages: 181-84
  • Peer Reviewed
• [Journal Article] Predicting pleural effusion and ascites following extended hepatectomy in the non-cirrhotic liver (2007)
  • Author(s): Shimizu Y, Sano T, Yasui K
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 837-840
• [Journal Article] Treatment strategy for synchronous metastases of colorectal cancer : Is hepatic resection after an observation interval appropriate? (2007)
  • Author(s): Shimizu Y, Yasui K, Sano T, Hirai T, Kanemitsu Y, Komori K, Kato T
  • Journal Title: Langenbeck's Arch Surg. 392 Pages: 535-538
• [Journal Article] Repeated hepatectomy for colonic liver metastasis presenting intrabiliary growth Application of percutaneous transhepatic portal vein embolization for impaired liver (2007)
  • Author(s): Hiramatsu K, Sano T, Nagino M, Nimura Y
  • Journal Title: Hepatogastroenterology 54 Pages: 1554-1556
• [Journal Article] Alterations of DNA Methylation and Histone Modifications Contribute to Gene Silencing in Hepatocellular Carcinomas (2007)
  • Author(s): Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, Kato H, Mizuno Y. Yokoe M, Sugauchi F, Hirashima H, Orito E, Osada H, Ueda R, Guo Y, Chen X, Issa JPJ, Sekido Y
  • Journal Title: Hepatol Res. 37 Pages: 974-83
  • NAID: 10019773990
• [Journal Article] a LIM gene on 5q31, is silenced by methylation in cancer and sensitizes cancer cells to apoptosis (2007)
  • Author(s): Boumber YA, Kondo Y, Chen X, Shen L, Gharibyan V, Konishi K, Estey E, Kantarjian H, Garcia-Manero G, Issa JP. RIL
  • Journal Title: Cancer Res. 67 Pages: 1997-2005
• [Journal Article] Genome-wide pro filing of DNA methylation reveals a class of normally methylated CpG island promoters (2007)
  • Author(s): Shen L, Kondo Y, Guo Y, ZhangJ, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP
  • Journal Title: Plos Genetics 3 Pages: 2023-36
• [Journal Article] Changing trends of surgical outcome of major hepatobiliary resection for hilar cholangiocarcinoma: a single center experience over 25 years. (2007)
  • Author(s): Sano T,
  • Journal Title: J Hepatobiliary Pancreat Surg 14 Pages: 456-456
  • Peer Reviewed
• [Journal Article] Surgery for hepatic neuroendocrine tumors: a single institutional experience in Japan. (2007)
  • Author(s): Hibi T,
  • Journal Title: Jpn J Clin Oncol 37 Pages: 525-529
  • Peer Reviewed
• [Journal Article] Surgical outcomes of the mass-forming plus periductal infiltrating type of intrahepatic cholangiocarcinoma: A comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. (2007)
  • Author(s): Shimada K,
  • Journal Title: World J Surg. 31 Pages: 2016-2022
  • Peer Reviewed
• [Presentation] Hepatobuiary resection for metastatic rectal cancer with an expandable metallic stent for obstructive jaundice (2009)
  • Author(s): Sano T, Shimizu Y, Senda Y, Ando M, Nimura Y
  • Organizer: The second biennial congress of the Asian-Pacific Hepato-Pancreato-Biliary Association
  • Place of Presentation: Bangkok, Thailand
• [Presentation] 大腸癌同時性肝転移に対する治療戦略-待機による肝切除成績と今後の展望- (2008)
  • Author(s): 清水泰博, 佐野力, 千田嘉毅, 安藤公隆, 山村義孝, 平井孝, 金光重秀, 伊藤誠二, 望月能成, 小森康司, 加藤知行, 二村雄次
  • Organizer: 第63回日本消化器外科学会総会 シンポジウム03 肝転移巣摘除のタイミング
  • Year and Date: 2008-07-17
• [Presentation] Variable DNA Methylation Patterns Associated with Progression of Disease in Hepatocellular Carcinoma (2008)
  • Author(s): Gao W, Kondo Y, Shen L, Shimizu Y, Sano T, Yamao K, Natsume A, Goto Y, Ito M, Murakami H, Osada H, Issa JPJ, Sekido Y
  • Organizer: The 2nd Shanghai Symposium of Epigenetics in Development and Diseases and The 3rd Annual Meeting of Asian Epigenome Alliance
  • Place of Presentation: Shanghai
  • Year and Date: 2008-07-06
• [Presentation] Treatment Strategy for Synchronous Metastases of Colorectal Cancer : Is Hepatic Resection After (2008)
  • Author(s): Shimizu Y
  • Organizer: 2008 DDW(SSAT)
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-05-17
• [Presentation] Treatment strategy for synchronous matastases of colorectal cancer : Is hepatic resection after an observation interval appropriate? (2008)
  • Author(s): Shimizu Y, Sano T, Yamao K, Nimura Y
  • Organizer: Digestive Disease Week 2008
  • Place of Presentation: San Diego, USA
• [Presentation] 化学療法後の大腸癌肝転移切除例における術前画像診断と病理学的所見の検討 (2008)
  • Author(s): 名嶋弥菜,稲葉吉隆,山浦秀和, 佐藤洋造, 清水泰博, 佐野力, 谷田部恭
  • Organizer: 第6回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 肝膵十二指腸切除(HPD)後にMRSA感染性大量腹水の管理に難渋した1例 (2007)
  • Author(s): 佐野 力、
  • Organizer: 第69回日本臨床外科学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-11-29
• [Presentation] 主膵管から共通管に進展した膵腺房細胞癌の1例 (2007)
  • Author(s): 佐野 力,
  • Organizer: 第69回日本臨床外科学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-11-29
• [Presentation] Genomewide DNA Methylation Analyses in Cancerous and Adjacent Tissues from Hepatocellular Carcinoma Patients (2007)
  • Author(s): An B, Kondo Y, Goto Y, Murakami H, Osada H, Sano T, Sekido Y
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] 肝細胞がん症例のがん部・背景肝部におけるDNAメチル化標的遺伝子の網羅的解析 (2007)
  • Author(s): 安炳九、
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] 膵胆管合流異常を伴った胆嚢原発小細胞癌の1切除例 (2007)
  • Author(s): 佐野 力,
  • Organizer: 第19回日本肝胆膵外科学会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2007-06-06
• [Presentation] 大腸癌同時性肝転移に対する治療戦略-待期による肝切除成績と治療法選択の変化- (2007)
  • Author(s): 清水泰博, 佐野力, 山村義孝, 平井孝, 金光幸秀, 伊藤誠二, 望月能成, 小森康司, 安藤公隆, 加藤知行
  • Organizer: 第62回日本消化器外科学会総会 2007 シンポジウム