Molecular mechanisms of DNA methylation alterations in precancerous conditions

• Project/Area Number: 23390096
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Cancer Center Japan
• Principal Investigator: KANAI Yae 独立行政法人国立がん研究センター, 研究所, 分野長 (00260315)
• Co-Investigator(Kenkyū-buntansha): ARAI Eri 国立研究開発法人国立がん研究センター研究所, 分子病理分野, 主任研究員 (40446547)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000); Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2011: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: DNAメチル化 / ヒストン修飾 / 前がん状態 / 腎がん / 肝がん / ヒストンメチル化酵素 / ヒストンアセチル化酵素 / ヒストンメチルトランスフェラーゼ / ヒストンアセチルトランスフェラーゼ / DNAメチルトランスフェラーゼ / 慢性肝炎 / 慢性閉塞性肺疾患 / 肺がん

Outline of Final Research Achievements

The aim of this study was to understand molecular mechanisms of DNA methylation alterations in precancerous conditions. Multi-layer omics abnormalities of histone methyltransferase, histone demethylase and histone acetyltransferase were observed in CpG islands methylator phenotype-positive renal cell carcinomas. H3K4me3 and H3K27Ac modifications preceded DNA methylation alterations at the chronic hepatitis and liver cirrhosis stages which are widely considered to be precancerous conditions for hepatocellular carcinomas. Histone modification alterations based on abnormalities of histone modification enzymes may be fixed due to DNA methylation alterations during multistage carcinogenesis and may determine aggressiveness of cancers.

Research Products

• [Journal Article] Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome. (2015)
  • Author(s): Yamanoi K, Arai E, Tian Y, Takahashi Y, Miyata S, Sasaki H, Chiwaki F, Ichikawa H, Sakamoto H, Kushima R, Katai H, Yoshida T, Sakamoto M, Kanai Y.
  • Journal Title: Carcinogenesis Volume: 36 Issue: 5 Pages: 509-520
  • DOI: 10.1093/carcin/bgv013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome. (2014)
  • Author(s): Arai E, Sakamoto H, Ichikawa H, Totsuka H, Chiku S, Gotoh M, Mori T, Nakatani T, Ohnami S, Nakagawa T, Fujimoto H, Wang L, Aburatani H, Yoshida T, Kanai Y.
  • Journal Title: Int J Cancer Volume: 135 Issue: 6 Pages: 1330-1342
  • DOI: 10.1002/ijc.28768
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic clustering of lung adenocarcinomas based on DNA methylation profiles in adjacent lung tissue: its correlation with smoking history and chronic obstructive pulmonary disease. (2014)
  • Author(s): Sato T, Arai E, Kohno T, Takahashi Y, Miyata S, Tsuta K, Watanabe S, Soejima K, Betsuyaku T, Kanai Y.
  • Journal Title: Int J Cancer Volume: in press Issue: 2 Pages: 319-334
  • DOI: 10.1002/ijc.28684
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome analysis. (2014)
  • Author(s): Gotoh M, Ichikawa H, Arai E, Chiku S, Sakamoto H, Fujimoto H, Hiramoto M, Nammo T, Yasuda K, Yoshida T, Kanai Y.
  • Journal Title: Genes Chromosomes Cancer Volume: 53 Issue: 12 Pages: 1018-1032
  • DOI: 10.1002/gcc.22211
  • Peer Reviewed / Open Access
• [Journal Article] Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes. (2014)
  • Author(s): Tian Y, Arai E, Gotoh M, Komiyama M, Fujimoto H, Kanai Y.
  • Journal Title: BMC Cancer Volume: 14 Issue: 1 Pages: 772-772
  • DOI: 10.1186/1471-2407-14-772
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Multilayer-omics analyses of human cancers: Exploration of biomarkers and drug targets based on the activities of the International Human Epigenome Consortium. (2014)
  • Author(s): Kanai Y, Arai E.
  • Journal Title: Front Genetics Volume: 5 Pages: 24-24
  • DOI: 10.3389/fgene.2014.00024
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation profiles at precancerous stages associated with recurrence of lung adenocarcinoma. (2013)
  • Author(s): Sato T, Arai E, Kohno T, Tsuta K, Watanabe S, Soejima K, Betsuyaku T, Kanai Y.
  • Journal Title: PLOS One Volume: 8(3) Issue: 3 Pages: e59444-e59444
  • DOI: 10.1371/journal.pone.0059444
  • Peer Reviewed
• [Journal Article] The tumor suppressor microRNA -29c is downregulated and restored by celecoxib in human gastric cancer cells (2013)
  • Author(s): Saito Y, Suzuki H, Imaeda H, Matsuzaki J, et al.
  • Journal Title: International Journal of Cancer Volume: 132 Issue: 8 Pages: 1751-1760
  • DOI: 10.1002/ijc.27862
  • Peer Reviewed
• [Journal Article] Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. (2012)
  • Author(s): Arai E, Kanai Y et al.
  • Journal Title: Carcinogenesis Volume: 33 Issue: 8 Pages: 1487-1493
  • DOI: 10.1093/carcin/bgs177
  • Peer Reviewed
• [Journal Article] DNA methyltransferase 3B expression is associated with pooroutcome of stage I testicular seminoma (2012)
  • Author(s): Aral E, Kanai Y, et al
  • Journal Title: Histopathology Volume: 60 Issue: 6B
  • DOI: 10.1111/j.1365-2559.2012.04174.x
  • Peer Reviewed
• [Journal Article] Higher-order chromatin regulation and differential gene expression in human TNF/LT locus in hepatocellular carcinoma cells (2012)
  • Author(s): Watanabe T.
  • Journal Title: Mol. Cell. Biol. Volume: 32 Issue: 8 Pages: 1529-1541
  • DOI: 10.1128/mcb.06478-11
  • Peer Reviewed
• [Journal Article] Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas (2012)
  • Author(s): Arai E, Kanai Y, et al
  • Journal Title: Carcinogenesis Volume: (In press)(未定)
  • Peer Reviewed
• [Journal Article] Copy number alterations in urothelial carcinomas : Their clinicopathological significance and correlation with DNA methylation alterations (2011)
  • Author(s): Nishiyama N, Inazawa J, et al
  • Journal Title: Carcinogenesis Volume: 32 Issue: 4 Pages: 462-469
  • DOI: 10.1093/carcin/bgq274
  • Peer Reviewed
• [Journal Article] Genome-wide DNA methylation profiles in renal tumors of various histological subtypes and non-tumorous renal tissues (2011)
  • Author(s): Arai E, Inazawa J, et al
  • Journal Title: Pathobiology Volume: 78 Issue: 1 Pages: 1-9
  • DOI: 10.1159/000322072
  • Peer Reviewed
• [Journal Article] Carcinogenetic risk estimation based on quantification of DNA methylation levels in liver tissue at the precancerous stage (2011)
  • Author(s): Nagashio R, Kondo Y, 6名
  • Journal Title: Int J Cancer Volume: 129 Issue: 5 Pages: 1170-1179
  • DOI: 10.1002/ijc.26061
  • Peer Reviewed
• [Journal Article] Diagnosis and prognostication of ductal adenocarcinomas of the pancreas based on genome-wide DNA methylation profiling by bacterial artificial chromosome array-based methylated CpG island amplification (2011)
  • Author(s): Gotoh M, Inazawa J, et al
  • Journal Title: J Biomed Biotechnol Volume: 2011 Issue: 1 Pages: 780836-780836
  • DOI: 10.1155/2011/780836
  • Peer Reviewed
• [Presentation] 多層的疾患オミックス解析におけるエピゲノム情報に基づく創薬標的の網羅的探索を目指した研究 (2015)
  • Author(s): 金井弥栄
  • Organizer: 彩都産学官連携フォーラム2015
  • Place of Presentation: 大阪
  • Year and Date: 2015-01-21
  • Invited
• [Presentation] 国際ヒトエピゲノムコンソーシアム (IHEC)における正常消化器上皮細胞等標準エピゲノムプロファイル決定 (2014)
  • Author(s): 金井弥栄
  • Organizer: 第59回日本人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-21
  • Invited
• [Presentation] Epigenome mapping of normal hepatocytes for understanding molecular background of human hepatocarcinogenesis. (2014)
  • Author(s): Yae Kanai.
  • Organizer: International Human Epigenome Consortium 2014
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-10-07
  • Invited
• [Presentation] 病理診断に付加価値を加える: 多層的オミックス解析にもとづく病態診断 (2014)
  • Author(s): 金井弥栄
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
  • Invited
• [Presentation] バイオバンク試料の利活用: 組織検体における多層オミックス解析. (2014)
  • Author(s): 金井弥栄
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-25
  • Invited
• [Presentation] Epigenome profiling during multistage human carcinogenesis and activities of International Human Epigenome Consortium (IHEC). (2013)
  • Author(s): Kanai Y
  • Organizer: 2013 Illumina Scientific Summit
  • Place of Presentation: Phuket, Thailand
  • Invited
• [Presentation] がんにおけるエピゲノム変化の解明と病態診断への応用. (2013)
  • Author(s): 金井弥栄
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 北海道札幌市ロイトン札幌ロイトンホールD
  • Invited
• [Presentation] 国際ヒトエピゲノムコンソーシアムの取り組み. (2013)
  • Author(s): 金井弥栄
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 神奈川県横浜市パシフィコ横浜311+312号室
  • Invited
• [Presentation] Multilayer-omics (whole-exome, methylome and transcriptome) analysis identifies the Wnt/β-catenin pathway as a key player in the development of renal cell carcinoma. (2013)
  • Author(s): Arai E, Sakamoto H, Ichikawa H, Totsuka H, Gotoh M, Mori T, Ohnami S, Nakagawa T, Fujimoto H, Wang L, Aburatani H, Yoshida T, and Kanai Y.
  • Organizer: 103rd American Association of Cancer Research Annual Meeting 2013
  • Place of Presentation: Washington DC, USA
• [Presentation] DNA methylation profiles at precancerous stage cluster lung adenocarcinomas into subclusters associated with carcinogenetic pathway, clinicopathological aggressiveness and patient outcome. (2013)
  • Author(s): Sato T, Arai E, Kohno T, Tsuta K, Watanabe S, Soejima K, Betsuyaku T and Kanai Y.
  • Organizer: 103rd American Association of Cancer Research Annual Meeting 2013
  • Place of Presentation: Washington DC, USA
• [Presentation] 肺多段階発がん過程におけるDNAメチル化異常のゲノム網羅的解析 (2012)
  • Author(s): 佐藤崇、金井弥栄, 他
  • Organizer: 第6回日本エピジェネティクス研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-15
• [Presentation] ゲノム網羅的DNAメチル化解析による腎淡明細胞がんのCpGアイランドメチル化形質 (2012)
  • Author(s): 新井恵吏、金井弥栄, 他
  • Organizer: 第6回日本エピジェネティクス研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-15
• [Presentation] 多層的オミックス解析による疾患の本態解明と臨床応用シンポジウム2「オミックス解析と病理学」 (2012)
  • Author(s): 金井弥栄
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2012-04-27
• [Presentation] 肺多段階発がん過程におけるDNAメチル化の変化のゲノム網羅的解析 (2012)
  • Author(s): 佐藤崇、金井弥栄, 他
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-27
• [Presentation] 腎細胞がん発生過程におけるDNAメチル化異常の網羅的解析 (2011)
  • Author(s): 新井恵吏、金井弥栄, 他
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] 腎細胞がん発生過程におけるDNAメチル化異常の網羅的解析 (2011)
  • Author(s): 新井恵吏、金井弥栄, 他
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本
  • Year and Date: 2011-05-20
• [Presentation] 慢性障害肝におけるDNAメチル化状態を指標とした発がんリスク評価の肝生検検体を用いた臨床応用 (2011)
  • Author(s): 長塩亮、金井弥栄, 他
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本
  • Year and Date: 2011-05-19
• [Presentation] 泌尿器系腫瘍及びその背景組織のメチル化解析.ワークショップ1前癌病変及び背景粘膜におけるエピジェネティックス異常 (2011)
  • Author(s): 新井恵吏、金井弥栄
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-04-28
• [Presentation] Copy number alterations in urothelial carcinomas : Their clinicopathological significance and correlation with DNA methylation alterations (2011)
  • Author(s): Naotaka Nishiyama, Yae Kanai, et al
  • Organizer: American Association for Cancer Research, 102nd Annual Meeting
  • Place of Presentation: オーランド(米国)
  • Year and Date: 2011-04-05
• [Presentation] Epigenome profiling during multistage human carcinogenesis and activities of International Human Epigenome Consortium (IHEC).
  • Author(s): Yae Kanai.
  • Organizer: 2013 Illumina Scientific Summit
  • Place of Presentation: Phuket, Thailand
  • Invited
• [Presentation] DNA methylation profiles at precancerous stage cluster lung adenocarcinomas into subclusters associated with carcinogenetic pathway, clinicopathological aggressiveness and patient outcome.
  • Author(s): Takashi Sato, Yae Kanai 他.
  • Organizer: 103rd American Association of Cancer Research Annual Meeting
  • Place of Presentation: Washington DC, USA
• [Presentation] Multilayer-omics (whole-exome, methylome and transcriptome) analysis identifies the Wnt/β-catenin pathway as a key player in the development of renal cell carcinoma.
  • Author(s): Eri Arai, Yae Kanai 他.
  • Organizer: 103rd American Association of Cancer Research Annual Meeting
  • Place of Presentation: Washington DC, USA
• [Presentation] Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.
  • Author(s): Eri Arai, Yae Kanai 他.
  • Organizer: 9th American Association of Cancer Research-Japanese Cancer Association Joint Conference
  • Place of Presentation: Hawaii, USA
• [Presentation] DNA methylation profiles at precancerous stages associated with recurrence of lung adenocarcinoma.
  • Author(s): Takashi Sato, Yae Kanai 他.
  • Organizer: 9th American Association of Cancer Research-Japanese Cancer Association Joint Conference
  • Place of Presentation: Hawaii, USA
• [Presentation] Epigenome profiling during multistage hepatocarcinogenesis and activities of International Human Epigenome Consortium (IHEC).
  • Author(s): Yae Kanai.
  • Organizer: 17th Japan-Korea Cancer Research Workshop
  • Place of Presentation: Busan, Korea
  • Invited
• [Presentation] 腎淡明細胞がんにおける多層的オミックス（エクソーム・メチローム・トランスクリプトーム）解析.
  • Author(s): 新井恵吏、金井弥栄 他.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 前がん段階におけるDNAメチル化異常が肺腺がんの悪性度と予後を規定する.
  • Author(s): 佐藤崇、金井弥栄 他.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 尿路上皮がんにおけるゲノム構造異常：臨床病理学的意義ならびにDNAメチル化異常との関係.
  • Author(s): 西山直隆、金井弥栄 他.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Standard epigenome analysis in digestive organs and research applications to multistage hepatocarcinogenesis.
  • Author(s): Yae Kanai 他.
  • Organizer: International Human Epigenome Consortium 2012
  • Place of Presentation: Soul, Korea
  • Invited
• [Presentation] ゲノム網羅的DNAメチル化解析による腎淡明細胞がんのCpGアイランドメチル化形質.
  • Author(s): 新井恵吏、金井弥栄 他.
  • Organizer: 第6回日本エピジェネティクス研究会
  • Place of Presentation: 東京
• [Presentation] 肺多段階発がん過程におけるDNAメチル化異常のゲノム網羅的解析.
  • Author(s): 佐藤崇、金井弥栄 他.
  • Organizer: 第6回日本エピジェネティクス研究会
  • Place of Presentation: 東京
• [Presentation] 多層的オミックス解析による疾患の本態解明と臨床応用. シンポジウム2「オミックス解析と病理学」
  • Author(s): 金井弥栄.
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 肺多段階発がん過程におけるDNAメチル化の変化のゲノム網羅的解析.
  • Author(s): 佐藤崇、金井弥栄 他.
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Book] ピジェネティクス―基礎研究から産業応用への展望― (2014)
  • Author(s): 金井弥栄, 新井恵吏.
  • Total Pages: 10
  • Publisher: シーエムシー出版
• [Book] DNA methylation alterations in human cancers. In: Epigenetics in Human Disease. (2012)
  • Author(s): Kanai Y et al.
  • Total Pages: 24
  • Publisher: Elsevier
• [Book] DNA methylation alterations in human cancers. In : Epigenetics in Human Disease (2012)
  • Author(s): Kanai Y, et al
  • Total Pages: 24
  • Publisher: Elsevier
• [Remarks] 国立がん研究センター研究所分子病理分野
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/01path/index.html
• [Remarks] 発がん機構研究グループ 分子病理分野
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/01path/index.html
• [Remarks] ヒト多段階発がん過程におけるエピゲノム異常
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/01path/01path01.html