Focal copy number alteration and its functional role in carcinogenesis: unmet needs in cancer genome analysis

• Project/Area Number: 17K07195
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: The University of Tokyo
• Principal Investigator: Kenji Tatsuno 東京大学, 先端科学技術研究センター, 特任研究員 (80775239)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: がんゲノム解析 / CNV / HBV / AAV2 / ロングリード解析 / ゲノム構造異常 / MSI / がんゲノム / ゲノム解析 / 癌

Outline of Final Research Achievements

We have developed a new analysis method of the next-generation sequencer (NGS) which can efficiently detect the focal copy number alterations (CNA) and viral genome integration in the cancer genome, which were difficult to detect with　conventional NGS analysis. With using this analysis, we have detected a large number of focal copy number alterations in mesotheliomas and virus integration in liver cancers. Furthermore, analysis using a long-read sequencer for mesothelioma and liver cancer revealed that genomic structural abnormalities occurred at the CNA regions and the integration site of the viral genome, which could be cancer driver alterations as well as known single nucleotide variations.

Academic Significance and Societal Importance of the Research Achievements

患者に最適な治療を行うプレシジョンメディシンが開始されているが、現時点では診断される遺伝子変異の種類は限られている。本研究は、これまで解析されてこなかった微小コピー数変化やウイルス挿入によるゲノム構造異常などの探索を、遺伝子パネル検査で使われる次世代シーケンサーの解析技術を応用することで可能とするものであり、がんに存在する多様な変異を逃すことなく解析することで、より精密ながん医療を実現を目指す。また、これまで未解明な部分が多かった微小なゲノム構造異常も、がん化に関連していることが明らかになり、本研究の手法を用いた解析がより詳細な発がんメカニズムの解明につながることが期待される。

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] 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] Base editors for simultaneous introduction of C-to-T and A-to-G mutations (2020)
  • Author(s): Sakata Rina C.、Ishiguro Soh、Mori Hideto、Tanaka Mamoru、Tatsuno Kenji、Ueda Hiroki、Yamamoto Shogo、Seki Motoaki、Masuyama Nanami、Nishida Keiji、Nishimasu Hiroshi、Arakawa Kazuharu、Kondo Akihiko、Nureki Osamu、Tomita Masaru、Aburatani Hiroyuki、Yachie Nozomu
  • Journal Title: Nature Biotechnology Volume: na Issue: 7 Pages: 865-869
  • DOI: 10.1038/s41587-020-0509-0
  • Peer Reviewed / Int'l Joint Research
• [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] 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] 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] 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] Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma. (2019)
  • Author(s): Nejo T, Matsushita H, Karasaki T, Nomura M, Saito K, Tanaka S, Takayanagi S, Hana T, Takahashi S, Kitagawa Y, Koike T, Kobayashi Y, Nagae G, Yamamoto S, Ueda H, Tatsuno K, Narita Y, Nagane M, Ueki K, Nishikawa R, Aburatani H, Mukasa A, Saito N, Kakimi K.
  • Journal Title: Cancer Immunol Res Volume: in press Issue: 7 Pages: 1148-1161
  • DOI: 10.1158/2326-6066.cir-18-0599
  • Peer Reviewed
• [Journal Article] Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis (2019)
  • Author(s): Matsuura Tetsuya、Maru Yoshiaki、Izumiya Masashi、Hoshi Daisuke、Kato Shingo、Ochiai Masako、Hori Mika、Yamamoto Shogo、Tatsuno Kenji、Imai Toshio、Aburatani Hiroyuki、Nakajima Atsushi、Hippo Yoshitaka
  • Journal Title: Carcinogenesis Volume: - Issue: 4 Pages: 1-12
  • DOI: 10.1093/carcin/bgz122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin‐fixed paraffin‐embedded specimens (2019)
  • Author(s): Kohsaka Shinji、Tatsuno Kenji、Ueno Toshihide、et al.
  • Journal Title: Cancer Science Volume: 110 Issue: 4 Pages: 1464-1479
  • DOI: 10.1111/cas.13968
  • Peer Reviewed / Open Access
• [Journal Article] Integrative Molecular Characterization of Malignant Pleural Mesothelioma (2018)
  • Author(s): Hmeljak Julija、TCGA Research Network et al (他58名、48番目)
  • Journal Title: Cancer Discovery Volume: 8 Issue: 12 Pages: 1548-1565
  • DOI: 10.1158/2159-8290.cd-18-0804
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes (2018)
  • Author(s): Hasumi Hisashi、Furuya Mitsuko、Tatsuno Kenji、Aburatani Hiroyuki、Linehan W Marston、Yao Masahiro, et al.
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 15 Pages: 2712-2724
  • DOI: 10.1093/hmg/ddy181
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic landscape influences the liver cancer genome architecture (2018)
  • Author(s): Natsuko Hama, Yasushi Totoki, Fumihito Miura, Kenji Tatsuno, Mihoko Saito-Adachi, Hiromi Nakamura, Yasuhito Arai, Fumie Hosoda, Tomoko Urushidate, Shoko Ohashi, Wakako Mukai, Nobuyoshi Hiraoka, Hiroyuki Aburatani , Takashi Ito and Tatsuhiro Shibata
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1643-1643
  • DOI: 10.1038/s41467-018-03999-y
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma (2017)
  • Author(s): Ally Adrian, Balasundaram Miruna,,,,Aburatani Hiroyuki, Yamamoto Shogo, Tatsuno Kenji,,,et al
  • Journal Title: Cell Volume: 169 Issue: 7 Pages: 1327-1341.e23
  • DOI: 10.1016/j.cell.2017.05.046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct molecular profile of diffuse cerebellar gliomas (2017)
  • Author(s): Nomura M, Mukasa A, Nagae G, Yamamoto S, Tatsuno K, Ueda H, Fukuda S, Umeda T, Suzuki T, Otani R, Kobayashi K, Maruyama T, Tanaka S, Takayanagi S, Nejo T, Takahashi S, Ichimura K, Nakamura T, Muragaki Y, Narita Y, Nagane M, Ueki K, Nishikawa R, Shibahara J, Aburatani H, Saito N
  • Journal Title: Acta Neuropathologica Volume: 134 Issue: 6 Pages: 941-956
  • DOI: 10.1007/s00401-017-1771-1
  • Peer Reviewed / Open Access
• [Presentation] ウイルスインテグレーションと肝がん (2020)
  • Author(s): 辰野 健二、緑川 泰、濱 奈津子、永江 玄太、上田 宏生、高山 忠利、柴田 龍弘、油谷 浩幸
  • Organizer: 第79回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] リキッドバイオプシーによる肝細胞がんのゲノム・エピゲノムプロファイリング (2019)
  • Author(s): 辰野健二、永江玄太、山本尚吾、福田史郎、緑川泰、高山忠利、油谷浩幸
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] All-in-one panel assay for clinical cancer sequencing (2018)
  • Author(s): Kenji Tatsuno, Shinji Kosaka, Hiroki Ueda, Shogo Yamamoto, Shuhei Yoshikawa, Toshihide Ueno, Takashi Aoki, Shiro Fukuda, Kunihiro Nishimura, Hiroyuki Mano, Hiroyuki Aburatani
  • Organizer: Precision Medicine in Cancer, Keystone Symposia
  • Int'l Joint Research
• [Presentation] Impact of Virus Integration into the Host Genome on Development of HCC in Patients with Occult HB Virus Infection (2018)
  • Author(s): Midorikawa Y, Tatsuno K, Takayama T, Yamamoto S, Nagae G, Moriyama M, Nakagawa H, Koike K, Moriya K, Aburatani H
  • Organizer: 第69回米国肝臓学会議
  • Int'l Joint Research
• [Presentation] オカルトB型肝炎ウイルス感染患者での肝細胞がんゲノムへのウイルスゲノム挿入部位解析 (2018)
  • Author(s): 辰野健二、緑川泰、高山忠利、永江玄太、山本尚吾、森山光彦、中川勇人、小池和彦、森屋恭爾、油谷浩幸
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Occult HBV肝癌患者におけるB型肝炎ウィルスDNA遺伝子組み込みの網羅的解析 (2018)
  • Author(s): 緑川泰、辰野健二、高山忠利、山本尚吾、永江玄太、森山光彦、小池和彦、森屋恭爾、油谷浩幸
  • Organizer: 第54回日本肝癌研究会
• [Presentation] Impact of virus integration into the genomes of hepatocellular carcinoma patients with prior hepatitis B virus infection (2018)
  • Author(s): Midorikawa Y, Tatsuno K, Yamamoto S, Nagae G, Koike K, Moriyama M, Takayama T, Moriya K, Aburatani H
  • Organizer: 米国がん学会
  • Int'l Joint Research
• [Presentation] 255症例の悪性胸膜中皮腫の網羅的遺伝子解析 (2018)
  • Author(s): 竹下純平，辰野健二，松本大地，栗林康造，近藤展行，長谷川誠紀，佐藤鮎子，辻村亨，大多茂樹，河上裕，中野孝司，関戸好孝，油谷浩幸
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 255検体悪性胸膜中皮腫の変異・免疫プロファイリング (2018)
  • Author(s): 竹下純平，辰野健二，山本尚吾，鈴木章浩，白石友一，栗林康造，近藤展行，長谷川誠紀，佐藤鮎子，辻村亨，松本大地，大多茂樹，河上裕，中野孝司，関戸好孝，油谷浩幸
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] 日本人胃癌の遺伝学的素因 (2018)
  • Author(s): 鈴木章浩、垣内美和子、田頭周、加藤洋人、竹下純平、山本尚吾、辰野健二、大島貴、利野靖、 中島淳、深山正久、石川俊平、 油谷浩幸
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] 卵巣明細胞癌における生殖細胞系・体細胞系ミスマッチ修復遺伝子異常 (2018)
  • Author(s): 織田克利、西島明、長谷川幸清、 浅田佳代、池田悠至、山本尚吾、永江玄太、辰野健二、黒崎亮、 藤原恵一、大須賀穣、藤井知行、 油谷浩幸
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] エクソームシーケンスデータからのマイクロサテライト不安定解析 (2017)
  • Author(s): 辰野 健二、吉川 修平、鈴木 章浩、山本 尚吾、永江 玄太、油谷 浩幸
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] ターゲットシークエンス検査による難聴患者の遺伝学的探索 (2017)
  • Author(s): 坂田 阿希、星 雄二郎、樫尾 明憲、 松本 有、山岨 達也、上田 宏生、 山本 尚吾、辰野 健二、油谷 浩幸
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] 243 症例の悪性胸膜中皮腫の統合的ゲノム解析 (2017)
  • Author(s): 竹下 純平、山本 尚吾、辰野 健二、白石 友一、大搗 泰一郎、 栗林 康造、近藤 展行、長谷川 誠紀、佐藤 鮎子、辻村 亨、中野 孝司、関戸 好孝、油谷 浩幸
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 日本人胃癌ゲノミックプロファイル (2017)
  • Author(s): 鈴木 章浩、垣内 美和子、田頭 周、加藤 洋人、山本 尚吾、 辰野 健二、酒井 英嗣、大島 貴、利野 靖、中島 淳、深山 正久、 石川 俊平、油谷 浩幸
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 高異型度卵巣漿液性癌における統合解析を用いた年齢シグネチャー優 位群の特徴付け (2017)
  • Author(s): 浅田 佳代、織田 克利、長谷川 幸清、西島 明、池田 悠至、 山本 尚吾、永江 玄太、辰野 健二、上田 宏生、藤原 恵一、大 須賀 穣、藤井 知行、油谷 浩幸
  • Organizer: 第76回日本癌学会学術総会
• [Book] がんゲノム医療遺伝子パネル検査実践ガイド (2020)
  • Author(s): 角南 久仁子
  • Total Pages: 240
  • Publisher: 医学書院
  • ISBN: 9784260042468