Multi-omics analysis for hepato-biliary-pancreatic cancers

• Project/Area Number: 18H04049
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Nakagawa Hidewaki 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (50361621)
• Co-Investigator(Kenkyū-buntansha): 井元 清哉 東京大学, 医科学研究所, 教授 (10345027) ; 山上 裕機 和歌山県立医科大学, 医学部, 教授 (20191190) ; 相方 浩 広島大学, 医系科学研究科(医), 准教授 (30403512) ; 中村 透 北海道大学, 医学研究院, 助教 (70645796) ; 二階堂 愛 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (00383290)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥44,330,000 (Direct Cost: ¥34,100,000、Indirect Cost: ¥10,230,000); Fiscal Year 2020: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000); Fiscal Year 2019: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2018: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
• Keywords: 肝胆膵がん / ゲノム / オミックス解析 / 分子分類 / 分子標的治療 / 腫瘍免疫 / 免疫 / ＲＮＡ / プロテオーム / ゲノム解析 / 多層オミックス / がんゲノム

Outline of Final Research Achievements

For liver cancer, we performed immune-genomic analysis and classified it into four subgroups in the aspects of immune suppression mechanism. Proteome analysis classified liver cancers in the aspects of drug therapies. We clarified the cellular plasticity mechanism of combined types of liver cancer with HCC and cholangiocarcinoma. For cholagiocarcinoma, we identified drugs which can be applicable in each patient by using genomic and transcriptomic data. For pancreatic cancer, we performed genomic and transcriptomic analysis with microbiome analysis on small intestine and examined any effect of chemotherapy on pancreatic cancer immunology and microbiome.

Academic Significance and Societal Importance of the Research Achievements

本研究は、最も難治性である肝胆膵がんに照準をしぼり、そのゲノム、RNA,たんぱく質、免疫、腸内細菌叢といった多元的なオミックス解析を行い、肝胆膵がんの分子分類を確立し、また、個別化治療の提案をおこなうものである。

Research Products

• [Int'l Joint Research] Samsung Medical Center(韓国)
• [Int'l Joint Research] Broad Institute/MD Anderson Cancer Center/NCI(米国)
• [Int'l Joint Research] Sanger Institute/Cambridge University/Cancer Res UK(英国)
• [Int'l Joint Research] 北京大学/ＢＧＩ(中国)
• [Int'l Joint Research] ソウル大学/サムソン病院/ＫＡＩＳＴ(韓国)
• [Int'l Joint Research] ベローナ大学(イタリア)
• [Int'l Joint Research]
• [Int'l Joint Research] 北京大学(中国)
• [Int'l Joint Research] ＭＤアンダーソンがんセンター(米国)
• [Journal Article] Whole genome sequencing with long-reads reveals complex structure and origin of structural variation in human genetic variations and somatic mutations in cancer. (2021)
  • Author(s): Fujimoto A, Wong JH, Yoshii Y, Akiyama S, Tanaka A, Yagi H, Shigemizu D, Nakagawa H, Mizokami M, and Shimada M.
  • Journal Title: Genome Medicine Volume: 13 Issue: 1 Pages: 65-65
  • DOI: 10.1186/s13073-021-00883-1
  • Peer Reviewed / Open Access
• [Journal Article] Tumor fibroblast growth factor receptor 4 level predicts the efficacy of Lenvatinib in patients with advanced hepatocellular carcinoma. (2020)
  • Author(s): Yamauchi M, Ono A, Ishikawa A, Kodama K, Uchikawa S, Hatooka H, Zhang P, Teraoka Y, Morio K, Fujino H, Nakahara T, Murakami E, Miki D, Kawaoka T, Tsuge M, Hiramatsu A, Imanura M, Hayes CN, Fujita M, Nakagawa H, Yusui W, Aikata H, and Chayama K.
  • Journal Title: Clin Transl Gastroenterology Volume: 11 Issue: 5 Pages: e00179-e00179
  • DOI: 10.14309/ctg.0000000000000179
  • Peer Reviewed
• [Journal Article] Neoantimon: A multifunctional R package for identification of tumor-specific neoantigens. (2020)
  • Author(s): Hasegawa T, Hayashi S, Nakagawa H, Miyano S, and Imoto S.
  • Journal Title: Bioinformatics Volume: 36 Issue: 18 Pages: 4813-4816
  • DOI: 10.1093/bioinformatics/btaa616
  • Peer Reviewed / Open Access
• [Journal Article] Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes (2020)
  • Author(s): Mizukami Keijiro、Iwasaki Yusuke、Kawakami Eiryo、Hirata Makoto、Kamatani Yoichiro、Matsuda Koichi、Endo Mikiko、Sugano Kokichi、Yoshida Teruhiko、Murakami Yoshinori、Nakagawa Hidewaki、Spurdle Amanda B.、Momozawa Yukihide
  • Journal Title: EBioMedicine Volume: 60 Pages: 103033-103033
  • DOI: 10.1016/j.ebiom.2020.103033
  • Peer Reviewed / Open Access
• [Journal Article] An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping (2020)
  • Author(s): Kawasaki K、Toshimitsu K、Matano M、Fujita M、Kudo Atsushi、Kitagawa Y、Kanai T、Nakagawa H、Sato T, et.al.
  • Journal Title: Cell Volume: 183 Issue: 5 Pages: 1420-1435
  • DOI: 10.1016/j.cell.2020.10.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic and transcriptomic landscape of gallbladder cancer for molecular classification and tumor microenvironment characterization. (2020)
  • Author(s): Ebata N, Fujita M, Sasagawa S, Maejima K, Okawa Y, Hatanaka Y, Mitsuhashi T, Oosawa A, Tanaka H, Miyano S, Nakamura T, Hirano S, and Nakagawa H
  • Journal Title: Cancers Volume: 13 Issue: 4 Pages: 733-733
  • DOI: 10.3390/cancers13040733
  • Peer Reviewed / Open Access
• [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] Analyses of non-coding somatic drivers in 2,658 cancer whole genomes (2020)
  • Author(s): PCAWG Consortium
  • Journal Title: Nature Volume: 578(7793) Issue: 7793 Pages: 102-111
  • DOI: 10.1038/s41586-020-1965-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Patterns of somatic structural variation in human cancer genomes. (2020)
  • Author(s): Li Y, Roberts ND, Wala JA, Shapira O, Schumacher SE, Kumar K, Khurana E, Waszak S, Korbel JO, Haber JE, Imielinski M; PCAWG Structural Variation Working Group, Weischenfeldt J, Beroukhim R, Campbell PJ; PCAWG Consortium.
  • Journal Title: Nature Volume: 578 Pages: 112-121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Repertoire of Mutational Signatures in Human Cancer. (2020)
  • Author(s): Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Ng AWT, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SM, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, the PCAWG Mutational Signatures Working Group, Getz G, Rozen SG. & Stratton MR.
  • Journal Title: Nature Volume: 578 Pages: 94-101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The landscape of viral associations in human cancers. (2020)
  • Author(s): Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, Desai N, Sültmann H, Moch H, PCAWG Pathogens Working Group, ICGC/TCGA Pan-cancer Analysis of Whole Genomes Network, Cooper CS, Eils R, Ferretti V, Peter Lichter P.
  • Journal Title: Nature Genetics Volume: 52 Issue: 3 Pages: 320-330
  • DOI: 10.1038/s41588-019-0558-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive molecular characterization of mitochondrial genomes in human cancers. (2020)
  • Author(s): Yuan Y, Ju YS, Kim Y, Li J, Wang Y, Yang Y, Martincorena I, Creighton CJ, Weinstein JN, Xu Y, Kim H, Nakagawa H, Park K, Campbell PJ, Liang H, on behalf of the PCAWG Mitochondrial Genome Working Group and The PCAWG Network.
  • Journal Title: Nature Genetics Volume: 52 Issue: 3 Pages: 342-352
  • DOI: 10.1038/s41588-019-0557-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations. (2020)
  • Author(s): Zhang Y, Chen F, Fonseca NA, He Y, Fujita M, Nakagawa H, Zhang Z, Brazma A, Creighton CJ, on behalf of the PCAWG Transcriptome Working Group, PCAWG Structural Variation Working Group, PCAWG Network
  • Journal Title: Nature Commun Volume: 11 Issue: 1 Pages: 736-736
  • DOI: 10.1038/s41467-019-13885-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations. (2020)
  • Author(s): Fujita M, Yamaguchi R, Hasegawa T, Shimada S, Arihiro K, Hayashi S, Maejima K, Nakano K, Fujimoto A, Ono A, Aikata H, Ueno M, Hayami S, Tanaka H, Miyano S, Yamaue H, Chayama K, Kakimi K, Tanaka S, Imoto S, Nakagawa H.
  • Journal Title: EBioMedicine Volume: 53 Pages: 102659-102659
  • DOI: 10.1016/j.ebiom.2020.102659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Somatic mutation landscape reveals differential variability of cell-of-origin for primary liver cancer. (2020)
  • Author(s): Ha KH, Fujita M, Karkic R, Yang S, Xue R, Zhang C, Bai F, Zhang N, Hoshida Y, Polak P, Nakagawa H, Kim HG, and Lee HJ
  • Journal Title: Heliyon Volume: 6 Issue: 2 Pages: e03350-e03350
  • DOI: 10.1016/j.heliyon.2020.e03350
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. (2020)
  • Author(s): Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, PCAWG et al
  • Journal Title: Nature Genet Volume: 52 Issue: 3 Pages: 306-319
  • DOI: 10.1038/s41588-019-0562-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Butler enables rapid cloud-based analysis of thousands of human genomes. (2020)
  • Author(s): Yakneen S, Waszak SM, PCAWG Technical Working Group, Gertz M & Korbel JO.
  • Journal Title: Nature Biotechnol. Volume: 38 Issue: 3 Pages: 288-292
  • DOI: 10.1038/s41587-019-0360-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing (2020)
  • Author(s): PCAWG Consortium
  • Journal Title: Nat Genet. Volume: 52(3) Issue: 3 Pages: 331-341
  • DOI: 10.1038/s41588-019-0576-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive Analysis of Indels in Whole-genome Microsatellite Regions and Microsatellite Instability across 21 Cancer Types (2020)
  • Author(s): Fujimoto A*, Fujita M, Hasegawa T, Wong JH, Maejima K, Oku-Sasaki A, Nakano K, Shiraishi Y, Miyano S, Yamamoto G, Akagi K, Imoto S, and Nakagawa H
  • Journal Title: Genome Research Volume: 30 Issue: 3 Pages: 334-34
  • DOI: 10.1101/gr.255026.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantifying immune-based counterselection of somatic mutations. (2019)
  • Author(s): Yang F, Kim DK, Nakagawa H, Hayashi S, Imoto S, Stein L, and Roth F
  • Journal Title: PLoS Genet Volume: 15 Issue: 7 Pages: e1008227-e1008227
  • DOI: 10.1371/journal.pgen.1008227
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas (2019)
  • Author(s): Mateos Raul N.、Nakagawa Hidewaki、Hirono Seiko、...、Fujita Masashi
  • Journal Title: Cancer Medicine Volume: 8 Issue: 10 Pages: 4565-4573
  • DOI: 10.1002/cam4.2340
  • Peer Reviewed / Open Access
• [Journal Article] Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes (2019)
  • Author(s): Xue Ruidong、Chen Lu、Zhang Chong、Fujita Masashi et al.
  • Journal Title: Cancer Cell Volume: 35 Issue: 6 Pages: 932-947
  • DOI: 10.1016/j.ccell.2019.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Whole Genome and Immuno-genomic Analysis of Liver Cancer (2020)
  • Author(s): Hidewaki Nakagawa
  • Organizer: 日本がん学会
  • Invited
• [Presentation] Immunogenomic analysis of liver cancer (2020)
  • Author(s): Masashi Fujita, Hidewaki Nakagawa
  • Organizer: 日本がん学会
  • Invited
• [Presentation] Genomic and transcriptomic landscape reveals molecular classification in gallbladder cancer (2020)
  • Author(s): Nobutaka Ebata, Hidewaki Nakagawa
  • Organizer: 日本がん学会
• [Presentation] Whole Genome and Immuno-genome Landscape of Liver Cancer (2019)
  • Author(s): Nakagawa H
  • Organizer: The Asian Pacific Association for the study of the liver (APASL) meeting, Tokyo
  • Int'l Joint Research / Invited
• [Presentation] Whole genome and immuno-genomic analysis of liver cancer (2019)
  • Author(s): Nakagawa H and Fujita M
  • Organizer: The 9th Asan Liver Center Symposium, Seoul, Korea
  • Int'l Joint Research / Invited
• [Presentation] Whole-Genome mutational landscape and characterization of non-coding and structural mutations in liver cancer (2019)
  • Author(s): Nakagawa H
  • Organizer: Gordon Research Conference, Hong Kong, China
  • Invited
• [Presentation] GEM Japan Updates (2019)
  • Author(s): Nakagawa H
  • Organizer: GA4GH 7th Plenary National Initiatives Workshop
  • Int'l Joint Research / Invited
• [Presentation] 胆道がんの網羅的ゲノム解析からゲノム医療へ (2019)
  • Author(s): 中川英刀、江畑信孝、平野聡
  • Organizer: 第55回日本胆道学会
  • Invited
• [Presentation] Whole genome and phosphor-proteomic analysis for liver cancers (2018)
  • Author(s): Nakagawa H
  • Organizer: The 8th RPPA Global Workshop
  • Int'l Joint Research / Invited
• [Presentation] Whole genome sequencing and immuno-genomic analysis for liver cancer (2018)
  • Author(s): Nakagawa H
  • Organizer: The 49th Princess Takamatsu Cancer Research Fund International Conference
  • Int'l Joint Research / Invited
• [Presentation] Pan-cancer Whole Genome Sequencing Project (PCAWG) in ICGC/TCGA (2018)
  • Author(s): Nakagawa H
  • Organizer: The 77th Annual Meeting of Japanese Cancer Association
  • Int'l Joint Research / Invited
• [Presentation] Cancer Whole Genome Sequencing and Immuno-genomic Analysis for Cancer (2018)
  • Author(s): Nakagawa H
  • Organizer: The 27th Korean Genome Organization Annual Conference
  • Int'l Joint Research / Invited
• [Presentation] Cancer Whole Genome Sequencing and Immuno-genomic Analysis for Cancer (2018)
  • Author(s): Nakagawa H
  • Organizer: KAIST Symposium
  • Int'l Joint Research / Invited