Compilation of somatic mutations using the clonality of iPS cells

• Project/Area Number: 16K07137
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: National Center for Child Health and Development
• Principal Investigator: OKAMURA Kohji 国立研究開発法人国立成育医療研究センター, システム発生・再生医学研究部, 室長 (80456194)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: iPS細胞 / 色素性乾皮症 / XPA / ERCC2 / ドライバー変異 / パッセンジャー変異 / 癌 / ゲノム / 変異 / クローニング

Outline of Final Research Achievements

Somatic mutations in cancers are either driver or passenger mutations. While a driver is within a gene that promotes cancer development, passengers are caused by its malignancy. It is important to identify a driver from an enormous number of mutations to understand the carcinogenesis. Because knowing patterns of passengers is also helpful in diagnose, prognosis, and treatment, methods to distinguish them are required. Unlike hereditary mutations, somatic mutations are usually buried in bulk and hard to be detected. Here, we established iPS cell lines from patients with DNA repair-deficient diseases, in which the causative germline mutation was employed as the driver, and performed whole-exome analyses. Making use of the clonality, we demonstrated a way to descrimnate the two types of mutations and found discrete features of mutations in ATM-, XPA-, and ERCC2-deficient cells, respectively, in terms of number, size, sequence context, and retrotransposition.

Academic Significance and Societal Importance of the Research Achievements

ドライバー変異とパッセンジャー変異の識別は困難で、多くの手法が提案されているがどれも予測にとどまる。また、低頻度の体細胞変異の検出にはかなりのシークエンシング量が要求されるという問題がある。本研究は、モザイク性とクローン性に着目し、上記2問題を解決するユニークでかつ強力な手法となった。がんは部位によって分類されていたが、関与する遺伝子で分類すべきである。またがんは変異群のプロファイリングによっても分類され、真のパッセンジャー変異を区別することで、いずれはドライバー変異との関係も明確になると期待され、これらの成果はがんの発生機序の理解から撲滅へと発展しうる、社会的にも意義深いものである。

Research Products

• [Journal Article] Whole transcriptome sequencing reveals a KMT2A‐USP2 fusion in infant acute myeloid leukemia (2019)
  • Author(s): Ikeda Junji、Shiba Norio、Tsujimoto Shin‐ichi、Yoshida Masanori、Nakabayashi Kazuhiko、Ogata‐Kawata Hiroko、Okamura Kohji、Takeuchi Masanobu、Osumi Tomoo、Tomizawa Daisuke、Hata Kenichiro、Kiyokawa Nobutaka、Ito Shuichi、Kato Motohiro
  • Journal Title: Genes, Chromosomes and Cancer Volume: in press Issue: 9 Pages: 1-1
  • DOI: 10.1002/gcc.22751
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion. (2019)
  • Author(s): Ohki K, Kiyokawa N, Hayashi Y, Koh K, Manabe A, Ohara A; Tokyo Children’s Cancer Study Group (TCCSG) et al.
  • Journal Title: Haematologica. Volume: 104(1) Issue: 1 Pages: 128-137
  • DOI: 10.3324/haematol.2017.186320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transient multifocal genomic crisis creating chromothriptic and non-chromothriptic rearrangements in prezygotic testicular germ cells (2019)
  • Author(s): Atsushi Hattori、Kohji Okamura、Yumiko Terada、Rika Tanaka、Yuko Katoh-Fukui、Yoichi Matsubara、Keiko Matsubara、Masayo Kagami、Reiko Horikawa、Maki Fukami
  • Journal Title: BMC Medical Genomics Volume: in press (MGNM-D-18-00350R2) Pages: 1-1
  • Peer Reviewed / Open Access
• [Journal Article] A novel KMT2A-ACTN2 fusion in infant B-cell acute lymphoblastic leukemia (2019)
  • Author(s): Masanori Yoshida、Kazuhiko Nakabayashi、Hiroko Ogata-Kawata、Tomoo Osumi、Shin-ichi Tsujimoto、Ryota Shirai、Kaoru Yoshida、Kohji Okamura、Kimikazu Matsumoto、Nobutaka Kiyokawa、Daisuke Tomizawa、Kenichiro Hata、Motohiro Kato
  • Journal Title: Pediatric Blood & Cancer Volume: in press (MPO27821) Issue: 8 Pages: 1-1
  • DOI: 10.1002/pbc.27821
  • Peer Reviewed / Open Access
• [Journal Article] 未来のゲノムデータベースから理解するディープラーニング (2019)
  • Author(s): 岡村浩司
  • Journal Title: 遺伝子医学 Volume: 9-3
  • NAID: 40021973517
• [Journal Article] Novel SIN3A mutation identified in a Japanese patient with Witteveen-Kolk syndrome (2018)
  • Author(s): Narumi-Kishimoto Yoko、Araki Naomi、Migita Ohsuke、Kawai Tomoko、Okamura Kohji、Nakabayashi Kazuhiko、Kaname Tadashi、Ozawa Yuri、Ozawa Hiroshi、Takada Fumio、Hata Kenichiro
  • Journal Title: European Journal of Medical Genetics Volume: in press Issue: 9 Pages: 1-1
  • DOI: 10.1016/j.ejmg.2018.09.014
  • Peer Reviewed / Open Access
• [Journal Article] RecurrentRARBTranslocations in Acute Promyelocytic Leukemia LackingRARATranslocation (2018)
  • Author(s): Osumi Tomoo、Tsujimoto Shin-ichi、Tamura Moe、Uchiyama Meri、Nakabayashi Kazuhiko、、Takita Junko（22ｔｈ）、Inukai Takeshi、Ogawa Seishi、Kitamura Toshio、Matsumoto Kimikazu、Hata Kenichiro、Kiyokawa Nobutaka、Goyama Susumu、Kato Motohiro
  • Journal Title: Cancer Research Volume: 78 Issue: 16 Pages: 4452-4458
  • DOI: 10.1158/0008-5472.can-18-0840
  • Peer Reviewed
• [Journal Article] Delayed Degradation and Impaired Dendritic Delivery of Intron-Lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc Transgenic Mice. (2018)
  • Author(s): Steward O, Matsudaira Yee K, Farris S, Pirbhoy PS, Worley P, Okamura K, Okuno H, Bito H.
  • Journal Title: Front Mol Neurosci. Volume: 10 Pages: 435-435
  • DOI: 10.3389/fnmol.2017.00435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An unclassified variant of CHD7 activates a cryptic splice site in a patient with CHARGE syndrome (2018)
  • Author(s): Katoh-Fukui Yuko、Yatsuga Shuichi、Shima Hirohito、Hattori Atsushi、Nakamura Akie、Okamura Kohji、Yanagi Kumiko、Iso Manami、Kaname Tadashi、Matsubara Yoichi、Fukami Maki
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 18006-18006
  • DOI: 10.1038/hgv.2018.6
  • Peer Reviewed / Open Access
• [Journal Article] Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes (2018)
  • Author(s): Okuno M.、Ayabe T.、Yokota I.、Musha I.、Shiga K.、Kikuchi T.、Kikuchi N.、Ohtake A.、Nakamura A.、Nakabayashi K.、Okamura K.、Momozawa Y.、Kubo M.、Suzuki J.、Urakami T.、Kawamura T.、Amemiya S.、Ogata T.、Sugihara S.、Fukami M.、the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes
  • Journal Title: Diabetic Medicine Volume: 35 Issue: 3 Pages: 376-380
  • DOI: 10.1111/dme.13566
  • Peer Reviewed
• [Journal Article] Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas (2017)
  • Author(s): Murakami Masanori、Yoshimoto Takanobu、Nakabayashi Kazuhiko、Nakano Yujiro、Fukaishi Takahiro、Tsuchiya Kyoichiro、Minami Isao、Bouchi Ryotaro、Okamura Kohji、Fujii Yasuhisa、Hashimoto Koshi、Hata Ken-ichiro、Kihara Kazunori、Ogawa Yoshihiro
  • Journal Title: Endocrine-Related Cancer Volume: 24 Issue: 10 Pages: 531-541
  • DOI: 10.1530/erc-17-0117
  • Peer Reviewed
• [Journal Article] Fetal Therapy Model of Myelomeningocele with Three-Dimensional Skin Using Amniotic Fluid Cell-Derived Induced Pluripotent Stem Cells (2017)
  • Author(s): Kajiwara Kazuhiro、Tanemoto Tomohiro、Wada Seiji、Karibe Jurii、Ihara Norimasa、Ikemoto Yu、Kawasaki Tomoyuki、Oishi Yoshie、Samura Osamu、Okamura Kohji、Takada Shuji、Akutsu Hidenori、Sago Haruhiko、Okamoto Aikou、Umezawa Akihiro
  • Journal Title: Stem Cell Reports Volume: 8 Issue: 6 Pages: 1701-1713
  • DOI: 10.1016/j.stemcr.2017.05.013
  • Peer Reviewed / Open Access
• [Journal Article] Potential roles of DNA methylation in the initiation and establishment of replicative senescence revealed by array-based methylome and transcriptome analyses (2017)
  • Author(s): M. Sakaki, Y. Ebihara, K. Okamura, K. Nakabayashi, A. Igarashi, K. Matsumoto, K. Hata, Y. Kobayashi, and K. Maehara
  • Journal Title: PLOS ONE Volume: 12(2) Issue: 2 Pages: e0171431-e0171431
  • DOI: 10.1371/journal.pone.0171431
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ZNF384-related fusion genes consist of a subgroup with a characteristic immunophenotype in childhood B-cell precursor acute lymphoblastic leukemia. (2017)
  • Author(s): Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura K, Yaguchi A, Terada K, Saito Y, Yoshimi A, Ogata-Kawata H, Sakamoto H, Kato M, Fujimura J, Hino M, Kinoshita A, Kakuda H, Kurosawa H, Kato K, Kajiwara R, Moriwaki K, Morimoto T, Nakamura K, Noguchi Y, Osumi T, Sakashita K, Takita J, et al.
  • Journal Title: Haematologica. Volume: 102 Issue: 1 Pages: 118-129
  • DOI: 10.3324/haematol.2016.151035
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome. (2017)
  • Author(s): Kagami M, Matsubara K, Nakabayashi K, Nakamura A, Sano S, Okamura K, Hata K, Fukami M, Ogata T.
  • Journal Title: Genet Med. Volume: 19 Issue: 4 Pages: 476-482
  • DOI: 10.1038/gim.2016.123
  • Peer Reviewed / Open Access
• [Journal Article] Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. (2016)
  • Author(s): Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K, Sakai A, Nakashima H, Hata K, Nakashima K, Hatada I
  • Journal Title: Nat Biotechnol. Volume: 34 Issue: 10 Pages: 1060-1065
  • DOI: 10.1038/nbt.3658
  • Peer Reviewed
• [Journal Article] In vivo maturation of human embryonic stem cell-derived teratoma over time (2016)
  • Author(s): Hidenori Akutsu, Michiyo Nasu, Shojiroh Morinaga, Teiichi Motoyama, Natsumi Honma, Masakazu Machida, Mayu Yamazaki-Inoue, Kohji Okamura, Kazuhiko Nakabayashi, Shuji Takada, Naoko Nakamura, Seiichi Kanzaki, Kenichiro Hata, and Akihiro Umezawa*
  • Journal Title: Regen. Ther. Volume: 5 Pages: 31-39
  • DOI: 10.1016/j.reth.2016.06.003
  • Peer Reviewed / Open Access
• [Journal Article] NR0B1 frameshift mutation in a boy with idiopathic central precocious puberty (2016)
  • Author(s): Hirohito Shima, Shuichi Yatsuga, Akie Nakamura, Shinichiro Sano, Takako Sasaki, Noriyuki Katsumata, Erina Suzuki, Kenichro Hata, Kazuhiko Nakabayashi, Yukihide Momozawa, Michiaki Kubo, Kohji Okamura, Shigeo Kure, Yoichi Matsubara, Tsutomu Ogata, Satoshi Narumi, and Maki Fukami*
  • Journal Title: Sex. Dev. Volume: 10 Issue: 4 Pages: 205-209
  • DOI: 10.1159/000448726
  • Peer Reviewed
• [Journal Article] Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b. (2016)
  • Author(s): Nakamura A, Hamaguchi E, Horikawa R, Nishimura Y, Matsubara K, Sano S, Nagasaki K, Matsubara Y, Umezawa A, Tajima T, Ogata T, Kagami M, Okamura K, Fukami M.
  • Journal Title: J Clin Endocrinol Metab Volume: 101(7) Issue: 7 Pages: 2623-7
  • DOI: 10.1210/jc.2016-1725
  • Peer Reviewed / Open Access
• [Journal Article] Distinctive features of single nucleotide alterations in induced pluripotent stem cells with different types of DNA repair deficiency disorders (2016)
  • Author(s): Kohji Okamura, Hironari Sakaguchi, Rie Sakamoto-Abutani, Mahito Nakanishi, Ken Nishimura, Mayu Yamazaki-Inoue, Manami Ohtaka, Vaiyapuri S. Periasamy, Ali A. Alshatwi, Akon Higuchi, Kazunori Hanaoka, Kazuhiko Nakabayashi, Shuji Takada, Kenichiro Hata, Masashi Toyoda, and Akihiro Umezawa*
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 26342-26342
  • DOI: 10.1038/srep26342
  • Peer Reviewed / Open Access
• [Journal Article] Human genetic variation database, a reference database of genetic variations in the Japanese population. (2016)
  • Author(s): Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, Doi K, Shimizu M, Nakabayashi K, Aoki Y, Tsurusaki Y, Morishita S, Kawaguchi T, Migita O, (中略), Matsumoto N, Matsuda F.
  • Journal Title: J Hum Genet. Volume: advance online publication Issue: 6 Pages: 547-553
  • DOI: 10.1038/jhg.2016.12
  • Peer Reviewed / Open Access
• [Journal Article] Lists of HumanMethylation450 BeadChip probes with nucleotide-variant information obtained from the Phase 3 data of the 1000 Genomes Project. (2015)
  • Author(s): Okamura K, Kawai T, Hata K, Nakabayashi K.
  • Journal Title: Genomics data Volume: 7 Pages: 67-9
  • DOI: 10.1016/j.gdata.2015.11.023
  • Peer Reviewed / Open Access
• [Journal Article] Complete genome sequence of the mitochondrial DNA of the sparkling enope squid, Watasenia scintillans (2015)
  • Author(s): Hayashi K, Kawai YL, Yura K, Yoshida MA, Ogura A, Hata K, Nakabayashi K, Okamura K
  • Journal Title: Mitochondrial DNA Volume: ? Issue: 3 Pages: 1842-1843
  • DOI: 10.3109/19401736.2014.971251
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Multifocal and multifaceted genomic crisis leading to highly complex chromosomal rearrangements in a boy with congenital disorders (2019)
  • Author(s): Atsushi Hattori, Kohji Okamura, Yumiko Terada, Rika Tanaka, Yuko Katoh-Fukui, Yoichi Matsubara, Keiko Matsubara, Masayo Kagami, Reiko Horikawa, Maki Fukami
  • Organizer: Pediatric Academic Societies Meeting 1801.15
  • Int'l Joint Research
• [Presentation] 第一期IRUD (希少・未診断疾患イニシアチブ) 統計と今後 (2018)
  • Author(s): 要 匡, 柳 久美子, 磯 まなみ, 小林 奈々, 阿部 幸美, 竹下 芽衣子, 黒木 陽子, 林 恵子, 岡村 浩司, 緒方-川田 広子, 河合 智子, 中林 一彦, 秦 健一郎, 小崎 健次郎, 佐藤 万仁, 松原 洋一
  • Organizer: 第41回日本分子生物学会年会 3P-0654
• [Presentation] 深層学習および線形分類を利用したトランススプライシングに関わる塩基配列の探索 (2018)
  • Author(s): 片桐 沙弥, 片桐 沙紀, 青砥 早希, 西野 光一郎, 岡村 浩司
  • Organizer: 第41回日本分子生物学会年会 2P-0170
• [Presentation] オリゴヌクレオチドの位置関係と畳み込みニューラルネットワークを利用したプロモーター配列の解析 (2018)
  • Author(s): 青砥 早希, 岡村 浩司
  • Organizer: 第41回日本分子生物学会年会 1PW1-12-3/2P-0169
  • Invited
• [Presentation] 細胞をリプログラミングすることで明らかにできたMMPファミリーの遺伝子発現機構 (2018)
  • Author(s): 片桐 沙紀, 高澤 建, 由良 敬, 堀家 慎一, 西野 光一郎, 岡村 浩司
  • Organizer: 第41回日本分子生物学会年会 2P-0138
• [Presentation] ゲノム塩基配列における特定塩基長の頻度情報を利用した深層学習による種分類 (2017)
  • Author(s): 片桐 沙紀, 岡村 浩司
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] 深層学習を利用したトランススプライシングに関わるゲノム領域の探索 (2017)
  • Author(s): 片桐 沙弥, 片桐 沙紀, 西野 光一郎, 岡村 浩司
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] ハイブリッドアセンブリによる健常日本人男性の全ゲノム配列決定 (2016)
  • Author(s): 岡村 浩司, 三浦 巧, 中林 一彦, 秦 健一郎, 佐藤 陽治, 梅澤 明弘
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
• [Patent(Industrial Property Rights)] 非破壊的な細胞解析方法 (2019)
  • Inventor(s): 梅澤明弘, 岡村浩司, 柴田眞侑, 野中秀紀, 山田雅雄, 他
  • Industrial Property Rights Holder: 梅澤明弘, 岡村浩司, 柴田眞侑, 野中秀紀, 山田雅雄, 他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-024097
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 細胞判定装置、細胞判定方法及びプログラム (2018)
  • Inventor(s): 西野光一郎, 新井, 梅澤, 阿久津, 岡村, 堀家, 犬塚
  • Industrial Property Rights Holder: 西野光一郎, 新井, 梅澤, 阿久津, 岡村, 堀家, 犬塚
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-034579
  • Filing Date: 2018