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: 中川 英刀 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: Granted (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: オミックス解析 / 肝胆膵がん / 免疫 / ゲノム / ＲＮＡ / プロテオーム / ゲノム解析 / 多層オミックス / 腫瘍免疫 / がんゲノム

Outline of Annual Research Achievements

300例の肝臓がんの全ゲノムシークエンスおよびRNAseqのデータを、国際連携でのがん全ゲノム解析プロジェクト（PCAWG）にて解析して、『Nature』に7報、『Nature Genetics』に5報など、多数の成果発表を行った。これら肝臓がんのデータを用いて免疫ゲノム統合解析を行い、肝臓がん内の免疫抑制機構に着目して、４つの免疫的分類を確立した。１つの群はTAM（マクロファージ）の存在が主要な免疫抑制機構であり、ARID２遺伝子の変異が関連していることを見出した。
さらには、290個の抗体を用いたRPPAによるプロテオームのデータを追加し、肝臓がんでのマルチキナーゼ阻害剤の標的となるpVEGFR2およびpFGFR4の発現データもELISA法によって取得した。これらの網羅的データ用いて、肝臓がんの分子標的薬適応の分類を行った（免疫チェックポイント阻害剤、マルチキナーゼ阻害剤、そして新規の標的分子）。
肝細胞がんと胆管がんが混在する特殊な「混合型肝がん」を主とする肝がんの統合的ゲノム解析、単一細胞解析を国際共同で行い、肝臓がんの新たな分子分類を確立し、混合型肝がんの分化過程での特徴を明らかにした。p53の下流で幹細胞の分化可塑性に関与するタンパク質Nestinの混合型肝がんの診断マーカーとして発見した。
胆嚢がん36例について、WGSおよびnon-coding RNAを含むRNAseqを施行し、微小環境の活性の強弱にて分類を行った。微小環境の影響が強い胆嚢がんはEMTや免疫細胞の活動が強く、TGFbシグナル分子の変異が多く見つかり、予後不良であった。
膵臓がんについては、術前化学放射線療法をうけて抵抗性となった40例の腫瘍と小腸の新鮮凍結サンプルを収集し、ゲノム解析を開始した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

肝臓がん、胆道がん、混合型腫瘍のmulti-omics解析を行い、それらのデータを統合解析し肝胆がんの分子分類、新規診断マーカー、そして、治療薬や治療標的薬を同定してきており、順調に研究がすすんでいる。多数の論文発表を行い、成果をあげてきている。

Strategy for Future Research Activity

肝臓がんのプロテオームのデータを含む統合解析を完成させ、新規の分子標的薬の同定を行い、機能解析のデータも取得する。
胆道がんのゲノム、ＲＮＡのデータより、最先端の知識データベース（ＫＢ）を利用して個別の分子標的薬の同定を行う。また、胆道癌組織内にいる微生物の同定、局所の免疫状態を推定する。
膵臓がんおよび小腸のゲノムおよびRNAデータより、膵臓がんの発生、化学療法の不反応性の機構を解明する。

Research Products

• [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] Pan-cancer analysis of whole genomes. (2020)
  • Author(s): The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium
  • Journal Title: Nature Volume: 578 Pages: 82-93
  • DOI: 10.1038/s41586-020-1969-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of non-coding somatic drivers in 2658 cancer whole genomes. (2020)
  • Author(s): PCAWG Consortium
  • Journal Title: Nature Volume: 578(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 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 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 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
  • 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 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 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: Nature Genet Volume: 52(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 Res Volume: 30 Pages: 2020-2020
  • 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
  • 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 Med Volume: 8 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 Pages: 932-947
  • DOI: 10.1016/j.ccell.2019.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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