Elucidation of molecular mechanism of carcinogenesis based on stratification of hereditary colorectal cancer

• Project/Area Number: 17K16530
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: The University of Tokyo
• Principal Investigator: Takane Kiyoko 東京大学, 医科学研究所, 助教 (60756112)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 家族性大腸腺腫症 / 大腸癌 / 大腸腺腫 / DNAメチル化 / 腺腫 / KRAS / BRAF / 大腸がん / エピジェネティクス / メチル化 / 大腸線腫 / Lynch症候群 / 家族性大腸ポリポーシス

Outline of Final Research Achievements

Familial adenomatous polyposis (FAP) is an inherited disorder characterized by numerous colorectal adenomatous polyps with predisposition to the development of colorectal cancer (CRC). Here, we conducted genome-wide DNA methylation analysis of FAP neoplasms. As controls for sporadic colorectal neoplasms and mucosae, we used data from CRC samples, colorectal adenoma samples, normal mucosa samples with reference to public databases. Unsupervised two-way hierarchical clustering analysis of FAP and sporadic CRC/adenoma revealed that CRC was classified into four DNA methylation epigenotypes. FAP neoplasms were classified into at least two molecular subtypes, i.e., normal like methylation type in the majority of cases showing mostly no aberrant methylation and intermediate methylation type in some cases accompanied by KRAS mutations but less frequent aberrant DNA methylation than sporadic neoplasms, suggesting that FAP may follow a tumorigenesis pathway different from that of sporadic CRC.

Academic Significance and Societal Importance of the Research Achievements

癌症例を詳細にサブタイプ分類し、各症例へ最も良い治療方針を即座に建立するテーラーメード癌治療概念は、癌を克服するための鍵として世界的に研究されている。我々は大腸癌の中でも高リスク群であり早期対応が望まれるにも関わらず疾患の選定や分子機構の解明に乏しかった家族性大腸腺腫症に対して同様の複合的解析を進め、家族性大腸腺腫症の層別化情報を診断や治療へ応用する。日本大腸癌研究会が近年、「遺伝性大腸癌診療ガイドライン」をあえて作成・周知している背景からも、この研究は遺伝性大腸癌の発癌機構解明に大きな寄与をもたらすだけでなく、これまで散発性大腸癌へ誤診されがちであった遺伝性大腸癌患者の救済にも貢献できる。

Research Products

• [Journal Article] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells (2019)
  • Author(s): Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Takane K, Shinozaki M, Tsurita G, Yano H, Furukawa Y
  • Journal Title: Oncogene Volume: 38(32) Issue: 32 Pages: 6051-6064
  • DOI: 10.1038/s41388-019-0856-9
  • Peer Reviewed
• [Journal Article] Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient (2019)
  • Author(s): Yamaguchi K, Shimizu E, Yamaguchi R, Imoto S, Komura M, Hatakeyama S, Noguchi R, Takane K, Ikenoue T, Gohda Y, Yano H, Miyano S, Furukawa Y
  • Journal Title: J Hum Genet. Volume: 64(8) Issue: 8 Pages: 729-740
  • DOI: 10.1038/s10038-019-0611-7
  • Peer Reviewed / Open Access
• [Journal Article] The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis. (2018)
  • Author(s): Takane K, Fukuyo M, Matsusaka K, Ota S, Rahmutulla B, Matsushita K, Miyauchi H, Nakatani Y, Matsubara H, Kaneda A.
  • Journal Title: Oncotarget. Volume: 9 Issue: 66 Pages: 32653-32666
  • DOI: 10.18632/oncotarget.25987
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of liquid-based genetic diagnosis of endometrial cancer. (2018)
  • Author(s): Matsuura M, Yamaguchi K, Tamate M, Satohisa S, Teramoto M, Iwasaki M, Sugita S, Hasegawa T, Koubo R, Takane K, Ikenoue T, Furukawa Y, Saito T.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 4025-4032
  • DOI: 10.1111/cas.13819
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation epigenotype and clinical features of NRAS-mutation(+) colorectal cancer. (2017)
  • Author(s): Takane K. Akagi K. Fukuyo M. Yagi K. Takayama T. Kaneda A.
  • Journal Title: Cancer Med Volume: 印刷中 Issue: 5 Pages: 1023-1035
  • DOI: 10.1002/cam4.1061
  • Peer Reviewed / Open Access
• [Journal Article] Frequent promoter hypermethylation associated with human papillomavirus infection in pharyngeal cancer. (2017)
  • Author(s): Nakagawa T, Matsusaka K, Misawa K, Ota S, Takane K, Fukuyo M, Rahmutulla B, Shinohara K, Kunii N, Sakurai D, Hanazawa T, Matsubara H, Nakatani Y, Okamoto Y, Kaneda A.
  • Journal Title: Cancer Letters Volume: 407 Pages: 21-31
  • DOI: 10.1016/j.canlet.2017.08.008
  • Peer Reviewed / Open Access
• [Journal Article] Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome. (2016)
  • Author(s): Hasegawa N, Oshima M, Sashida G, Matsui H, Koide S, Saraya A, Wang C, Muto T, Takane K, Kaneda A, Shimoda K, Nakaseko C, Yokote K, Iwama A.
  • Journal Title: Leukemia Volume: in press Issue: 4 Pages: 861-871
  • DOI: 10.1038/leu.2016.268
  • Peer Reviewed / Int'l Joint Research
• [Presentation] The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis. (2018)
  • Author(s): Kiyoko Takane, Masaki Fukuyo, Keisuke Matsusaka, Satoshi Ota, Bahityar Rahmutulla, Kazuyuki Matsushita, Hideaki Miyauchi, Yukio Nakatani, Hisahiro Matsubara, Atsushi Kaneda.
  • Organizer: FAP研究会学術集会
• [Presentation] The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis. (2018)
  • Author(s): Kiyoko Takane, Masaki Fukuyo, Keisuke Matsusaka, Satoshi Ota, Bahityar Rahmutulla, Kazuyuki Matsushita, Hideaki Miyauchi, Yukio Nakatani, Hisahiro Matsubara, Atsushi Kaneda.
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] 家族性大腸腺腫症の大腸腫瘍におけるプロモーターメチル化頻度の減少 (2018)
  • Author(s): 高根希世子、福世真樹、松坂恵介、太田聡、バハテヤリ・ラヒムトラ、松下一之、宮内英聡、中谷行雄、松原久裕、金田篤志
  • Organizer: 第29回日本消化器癌発生学会総会
• [Presentation] Two subtypes with distinct molecular features in colorectal tumor of familial adenomatous polyposis (2017)
  • Author(s): Kiyoko Takane, Keisuke Matsusaka, Satoshi Ota, Masaki Fukuyo, Yao Yue, Motoi Nishimura, Eiji Sakai, Kazuyuki Matsushita, Hideaki Miyauchi, Hiroyuki Aburatani, Yukio Nakatani, Tadatoshi Takayama, Hisahiro Matsubara, Kiwamu Akagi, Atsushi Kaneda
  • Organizer: 第76回日本学会学術総会
• [Presentation] Correlation between gene promoter hypermethylation and prognosis in pharyngeal cancer (2017)
  • Author(s): Takuya Nakagawa, Keisuke Matsusaka, Kiyoshi Misawa, Kiyoko Takane, Masaki Fukuyo, Satoshi Ota, Bahityar Rahmutulla, Naoki Kunii, Daiju Sakurai, Toyoyuki Hanazawa, Yukio Nakatani, Yoshitaka Okamoto, Atsushi Kaneda
  • Organizer: 第76回日本学会学術総会
• [Presentation] Genetic and epigenetic alteration in malignant melanoma (2017)
  • Author(s): Yosuke Yamamoto, Keisuke Matsusaka, Kiyoko Takane, Masaki Fukuyo, Satoshi Ota, Hiroyuki Matsue, Atsushi Kaneda
  • Organizer: 第76回日本学会学術総会
• [Presentation] Two subtypes with distinct molecular features in colorectal tumor of familial adenomatous polyposis (2017)
  • Author(s): Kiyoko Takane, Keisuke Matsusaka, Satoshi Ota, Masaki Fukuyo, Yao Yue, Motoi Nishimura, Eiji Sakai, Kazuyuki Matsushita, Hideaki Miyauchi, Hiroyuki Aburatani, Yukio Nakatani, Tadatoshi Takayama, Hisahiro Matsubara, Kiwamu Akagi, Atsushi Kaneda
  • Organizer: 第28回日本消化器癌発生学会総会
• [Book] エピジェネティクス実験スタンダード もう悩まない！ ゲノム機能制御の読み解き方 (2017)
  • Author(s): 牛島俊和，眞貝洋一，塩見春彦
  • Total Pages: 398
  • Publisher: 羊土社
• [Remarks] 消化器がんの発生、進展メカニズム解明
  • URL: https://www.ims.u-tokyo.ac.jp/furukawa/research/