Cellular deconvolution analysis of hepatocellular carcinoma based on the systemic epigenomic profiles

• Project/Area Number: 18K07963
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Nagae Genta 東京大学, 先端科学技術研究センター, 講師 (10587348)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝がん / DNAメチル化 / 微小環境 / 肝癌 / 細胞不均一性 / 一細胞解析 / 肝細胞癌

Outline of Final Research Achievements

We established and validated a method to accurately quantify the composition of cancerous and non-cancerous cells comprising the clinical liver cancer tissues. Cell deconvolution was performed in a mixed linear model to estimate the compositional ratio of various cells and the pure methylation rate of individual cells. When implemented in a multi-omics analysis of liver clinical tissues, it was found that the percentage of tumor cell fraction estimated by LUMP method were well correlated with the result of epithelial cell fraction in this approach. The subgroups (E4) with fewer tumor cell components identified by hierarchical clustering of bulk methylation data tended to be dominated by CD4+ and CD8+ T cells, monocytes and macrophage-like cells.

Academic Significance and Societal Importance of the Research Achievements

肝癌組織の一部には間質の増生や炎症細胞浸潤の高いものも存在するが、こうした症例はしばしば大規模プロジェクトの対象外とされてきたため、ドライバー変異を含む分子プロファイルとの関係が明らかでない。本研究課題で開発した推定法により、こうした症例も含めたあらゆる肝癌組織の分子プロファイルを対象にしうると考えられた。また、非癌細胞の構成比率を明らかにすることで、癌細胞の純粋なメチル化プロファイルを逆算することも可能となり、新たなエピゲノム制御異常が解明できる可能性がある。

Research Products

• [Journal Article] Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples (2020)
  • Author(s): Bailey Matthew H., et al.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4748-4748
  • DOI: 10.1038/s41467-020-18151-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sex differences in oncogenic mutational processes (2020)
  • Author(s): Li Constance H.、PCAWG Tumour Subtypes and Clinical Translation、Prokopec Stephenie D.、Sun Ren X.、Yousif Fouad、Schmitz Nathaniel、Boutros Paul C.、PCAWG Consortium
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4330-4330
  • DOI: 10.1038/s41467-020-17359-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression (2020)
  • Author(s): Midorikawa Yutaka、(17名）Aburatani Hiroyuki
  • Journal Title: Cancer Research Volume: 80 Issue: 18 Pages: 3810-3819
  • DOI: 10.1158/0008-5472.can-20-0225
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel sensitive detection method for DNA methylation in circulating free DNA of pancreatic cancer (2020)
  • Author(s): Shinjo K, Hara K, Nagae G, Umeda T, Katsushima K, Suzuki M, Murofushi Y, Umezu Y, Takeuchi I, Takahashi S, Okuno Y, Matsuo K, Ito H, Tajima S, Aburatani H, Yamao K, Kondo Y.
  • Journal Title: PLoS One Volume: 15 Issue: 6 Pages: 0233782-0233782
  • DOI: 10.1371/journal.pone.0233782
  • Peer Reviewed / Open Access
• [Journal Article] Defined lifestyle and germline factors predispose Asian populations to gastric cancer (2020)
  • Author(s): Suzuki A, Katoh H, Komura D, Kakiuchi M, Tagashira A, Yamamoto S, Tatsuno K, Ueda H, Nagae G, Fukuda S, Umeda T, Totoki Y, Abe H, Ushiku T, Matsuura T, Sakai E, Ohshima T, Nomura S, Seto Y, Shibata T, Rino Y, Nakajima A, Fukayama M, Ishikawa S, Aburatani H.
  • Journal Title: Science Advances Volume: 6 Issue: 19 Pages: 9778-9778
  • DOI: 10.1126/sciadv.aav9778
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation (2020)
  • Author(s): A. Nishiyama, C. Mulholland, S. Bultmann, S. Kori, A. Endo, Y. Saeki, W. Qin, C. Trummer, Y. Chiba, H. Yokoyama, S. Kumamoto, T. Kawakami, H. Hojo, G. Nagae, H. Aburatani, K. Tanaka, K. Arita, H. Leonhardt, M. Nakanishi
  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 1222-1222
  • DOI: 10.1038/s41467-020-15006-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pan-cancer analysis of whole genomes (2020)
  • Author(s): The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium
  • Journal Title: Nature Volume: 578 Issue: 7793 Pages: 82-93
  • DOI: 10.1038/s41586-020-1969-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spatial and temporal expansion of intrahepatic metastasis by molecularly‐defined clonality in multiple liver cancers (2020)
  • Author(s): Yamamoto Shogo、Midorikawa Yutaka、Nagae Genta、Tatsuno Kenji、Ueda Hiroki、Moriyama Mitsuhiko、Takayama Tadatoshi、Aburatani Hiroyuki
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 601-609
  • DOI: 10.1111/cas.14282
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells (2019)
  • Author(s): Nakato R, Wada Y, Nakaki R, Nagae G, Katou Y, Tsutsumi S, Nakajima N, Fukuhara H, Iguchi A, Kohro T, Kanki Y, Saito Y, Kobayashi M, Izumi-Taguchi A, Osato N, Tatsuno K, Kamio A, Hayashi-Takanaka Y, Wada H, Ohta S, Aikawa M, Nakajima H, Nakamura M, McGee RC, Heppner KW, Kawakatsu T, Genno M, Yanase H, Kume H, et al.
  • Journal Title: Epigenetics & Chromatin Volume: 12 Issue: 1 Pages: 77-77
  • DOI: 10.1186/s13072-019-0319-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection (2019)
  • Author(s): Tatsuno Kenji、Midorikawa Yutaka、Takayama Tadatoshi、Yamamoto Shogo、Nagae Genta、Moriyama Mitsuhiko、Nakagawa Hayato、Koike Kazuhiko、Moriya Kyoji、Aburatani Hiroyuki
  • Journal Title: Clinical Cancer Research Volume: 25 Issue: 20 Pages: 6217-6227
  • DOI: 10.1158/1078-0432.ccr-18-4041
  • Peer Reviewed
• [Journal Article] DNA demethylation is associated with malignant progression of lower-grade gliomas (2019)
  • Author(s): Nomura Masashi、Saito Kuniaki、Aihara Koki、Nagae Genta、Yamamoto Shogo、Tatsuno Kenji、Ueda Hiroki、Fukuda Shiro、Umeda Takayoshi、Tanaka Shota、…、Narita Yoshitaka、Nagane Motoo、Nishikawa Ryo、Ueki Keisuke、Saito Nobuhito、Aburatani Hiroyuki、Mukasa Akitake
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1903-1903
  • DOI: 10.1038/s41598-019-38510-0
  • URL: https://pure.teikyo.jp/en/publications/2263a84d-582c-4ced-a70e-ddc38d92ac65
  • Peer Reviewed / Open Access
• [Journal Article] Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer (2019)
  • Author(s): Namba Shinichi、Sato Kazuhito、Kojima Shinya、Ueno Toshihide、Yamamoto Yoko、Tanaka Yosuke、Inoue Satoshi、Nagae Genta、Iinuma Hisae、Hazama Shoichi、Ishihara Soichiro、Aburatani Hiroyuki、Mano Hiroyuki、Kawazu Masahito
  • Journal Title: Cancer Science Volume: 110 Issue: 3 Pages: 1096-1104
  • DOI: 10.1111/cas.13937
  • Peer Reviewed / Open Access
• [Journal Article] Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation (2018)
  • Author(s): Nakayama Chiemi、Yamamichi Nobutake、Tomida Shuta、Takahashi Yu、Kageyama-Yahara Natsuko、Sakurai Kouhei、Takeuchi Chihiro、Inada Ken-ichi、Shiogama Kazuya、Nagae Genta、Ono Satoshi、Tsuji Yosuke、Niimi Keiko、Fujishiro Mitsuhiro、Aburatani Hiroyuki、Tsutsumi Yutaka、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3853-3864
  • DOI: 10.1111/cas.13821
  • Peer Reviewed / Open Access
• [Journal Article] Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability?High Colorectal Cancers (2018)
  • Author(s): Sato Kazuhito、Kawazu Masahito、Yamamoto Yoko、Ueno Toshihide、Kojima Shinya、Nagae Genta、Abe Hiroyuki、Soda Manabu、Oga Takafumi、Kohsaka Shinji、Sai Eirin、Yamashita Yoshihiro、Iinuma Hisae、Fukayama Masashi、Aburatani Hiroyuki、Watanabe Toshiaki、Mano Hiroyuki
  • Journal Title: Clinical Cancer Research Volume: 25 Issue: 1 Pages: 378-389
  • DOI: 10.1158/1078-0432.ccr-18-1574
  • Peer Reviewed
• [Journal Article] Integrated molecular profiling of juvenile myelomonocytic leukemia (2018)
  • Author(s): Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H
  • Journal Title: Blood Volume: 131 Issue: 14 Pages: 1576-1586
  • DOI: 10.1182/blood-2017-07-798157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Distinct subgroups of hepatoblastoma related to prolonged Wnt-signal activation and “cell of origin” methylation signatures (2020)
  • Author(s): Nagae G, Yamamoto S, Fujita M, Nakagawa H, Aburatani H, Hiyama E
  • Organizer: The 79th Japan Cancer Association Annual Meeting
  • Int'l Joint Research
• [Presentation] 網羅的ゲノム・エピゲノム情報 を駆使したがん研究の最前線 (2020)
  • Author(s): 永江 玄太
  • Organizer: 日本人類遺伝学会第65回大会
  • Invited
• [Presentation] Molecular landscape of Hepatoblastoma (2019)
  • Author(s): Nagae G, Yamamoto S, Fujita M, Tatsuno K, Nakagawa H, Hiyama E, Aburatani H
  • Organizer: 第78回日本癌学会学術総会
  • Int'l Joint Research
• [Presentation] Specific roles and regulation of TET1 in epithelial carcinoma (2019)
  • Author(s): Genta Nagae
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Feasibility and clinical usefulness of detecting aberrant methylation in cell-free DNA (2018)
  • Author(s): Genta Nagae, Satoshi Ohta, Takayoshi Umeda, Yutaka Midorikawa, Hiroyuki Aburatani
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research / Invited