計算とシミュレーションによるがんシステム学の創成

2014 Fiscal Year Annual Research Report

• Project Area: Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention
• Project/Area Number: 22134004
• Research Institution: The University of Tokyo
• Principal Investigator: 宮野 悟 東京大学, 医科学研究所, 教授 (50128104)
• Co-Investigator(Kenkyū-buntansha): 井元 清哉 東京大学, 医科学研究所, 准教授 (10345027) ; 山口 類 東京大学, 医科学研究所, 講師 (90380675) ; 白石 友一 東京大学, 医科学研究所, 助教 (70516880) ; 玉田 嘉紀 東京大学, 情報理工学(系)研究科, 助教 (80435495) ; 島村 徹平 名古屋大学, 医学(系)研究科(研究院), 特任准教授 (00623943)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: がん / システム生物学 / ゲノム科学 / バイオインフォマティクス / 統計的モデリング

Outline of Annual Research Achievements

がんのｼｽﾃﾑ的統合理解のために、新たなｼｽﾃﾑ的方法論、及び、その応用として以下の主要な成果を得た。
(1)NetworkProfiler (Shimamura T, et al. PLoS One)は、Lassoﾀｲﾌﾟの正則化推定法に基づき、ﾓｼﾞｭﾚｰﾀのｽｺｱが付与された多ｻﾝﾌﾟﾙの遺伝子発現ﾌﾟﾛﾌｧｲﾙﾃﾞｰﾀから、それぞれのｻﾝﾌﾟﾙの遺伝子ﾈｯﾄﾜｰｸを推定する方法であるが、外れ値に対して弱いという問題点があった。そこで、このLassoﾀｲﾌﾟの正則化推定法の問題点を同定し、予測能力向上と変数選択の正確性を同時に高めることに成功し、外れ値に対してロバストな遺伝子ﾈｯﾄﾜｰｸ推定方法を開発した。この方法を、Sanger Instituteから公開されている700以上のがん細胞株の遺伝子発現ﾌﾟﾛﾌｧｲﾙﾃﾞｰﾀと100以上の薬剤に対するIC50ﾃﾞｰﾀに適用し、101の薬剤のそれぞれに対して、個々のがん細胞株の薬剤感受性・耐性に関する遺伝子ﾈｯﾄﾜｰｸを推定した。この薬剤感受性・耐性遺伝子ﾈｯﾄﾜｰｸ解析結果から、個々の検体に対する薬剤耐性・感受性ﾊﾞｲｵﾏｰｶｰの推定と耐性・感受性を高精度に予測することができた。
(2)ｼｰｸｴﾝｽﾃﾞｰﾀの解析手法については、低アレル頻度でも高い検出力を有する体細胞変異同定できるﾍﾞｲｼﾞｱﾝ･ﾊｲｴﾗｷｰ法(ｿﾌﾄｳｪｱ名:HapMuc)を新たに開発した。ｼﾐｭﾚｰｼｮﾝﾃﾞｰﾀ、TCGA Mutation Calling Benchmark 4 datasets、 data COLO-829細胞株ﾃﾞｰﾀを用いて、これまで発表され使われている他の方法との比較実験で、この方法はspecificityとsensitivityの両面で他の方法より優れていることが示された。
(3)22の hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) 検体とそのｺﾝﾄﾛｰﾙの全ｹﾞﾉﾑｼｰｸｴﾝｽﾃﾞｰﾀ及びRNAｼｰｸｴﾝｽﾃﾞｰﾀの統合比較解析を行った結果、ｹﾞﾉﾑ変異から非常に多様なﾄﾗﾝｽｸﾘﾌﾟﾄｰﾑの変異が明らかになった。
(4)班員、及び連携研究者等との共同研究を多数実施し、ｽｰﾊﾟｰｺﾝﾋﾟｭｰﾀとこれまでに開発した解析ﾊﾟｲﾌﾟﾗｲﾝを用い、がん病態の原因遺伝子及びその変異の探索に貢献した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Genomon ITDetector: A tool for somatic internal tandem duplication detection from cancer genome sequencing data. Bioinformatics (2015)
  • Author(s): Chiba K, Shiraishi Y, Nagata Y, Yoshida K, Imoto S, Ogawa S, Miyano S.
  • Journal Title: Bioinformatics Volume: 31(1) Pages: 116-118
  • Peer Reviewed / Open Access
• [Journal Article] Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity (2015)
  • Author(s): Fujimoto A, Furuta M, Shiraishi Y, Gotoh K, Kawakami Y, Arihiro K, Nakamura T, Ueno M, Ariizumi SI, Hai Nguyen H, Shigemizu D, Abe T, Boroevich KA, Nakano K, Sasaki A, Kitada R, Maejima K, Yamamoto Y, Tanaka H, Shibuya T, Shibata T, Ojima H, Shimada K, Hayami S, Shigekawa Y, Aikata H, Ohdan H, Marubashi S, et al.
  • Journal Title: Nat Commun. Volume: 6 Pages: 6120
  • Peer Reviewed / Open Access
• [Journal Article] PRPF8 defects cause missplicing in myeloid malignancies (2015)
  • Author(s): Kurtovic-Kozaric A, Przychodzen B, Singh J, Konarska MM, Clemente MJ, Otrock ZK, Nakashima M, Hsi ED, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Boultwood J, Makishima H, Maciejewski JP, Padgett RA
  • Journal Title: Leukemia Volume: 29(1) Pages: 126-136
  • Peer Reviewed / Open Access
• [Journal Article] Genomic data assimilation using a higher moment filtering technique for restoration of gene regulatory networks (2015)
  • Author(s): Hasegawa T, Mori T, Yamaguchi R, Shimamura T, Miyano S, Imoto S, Akutsu T
  • Journal Title: MC Syst Biol Volume: 9(1) Pages: 14
  • Peer Reviewed / Open Access
• [Journal Article] Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features (2014)
  • Author(s): Arima C, Kajino T, Tamada Y, Imoto S, Shimada Y, Nakatochi M, Suzuki M, Isomura H, Yatabe Y, Yamaguchi T, Yanagisawa K, Miyano S, Takahashi T
  • Journal Title: Carcinogenesis Volume: 35(10) Pages: 2224-2231
  • Peer Reviewed / Open Access
• [Journal Article] Tracing the development of acute myeloid leukemia in CBL syndrome (2014)
  • Author(s): Becker H, Yoshida K, Blagitko-Dorfs N, Claus R, Pantic M, Abdelkarim M, Niemoller C, Greil C, Hackanson B, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Dohner K, Schnittger S, Henneke P, Niemeyer CM, Flotho C, Pfeifer D, Ogawa S, Lubbert M
  • Journal Title: Blood Volume: 123(12) Pages: 1883-1886
  • Peer Reviewed / Open Access
• [Journal Article] Acquired initiating mutations in early hematopoietic cells of CLL patients (2014)
  • Author(s): Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E, Diop M, Scourzic L, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kikushige Y, Davi F, Lambert J, Gautheret D, Merle-Beral H, Sutton L, Dessen P, Solary E, Akashi K, Vainchenker W, Mercher T, Droin N, Ogawa S, Nguyen-Khac F, Bernard OA
  • Journal Title: Cancer Discov Volume: 4(9) Pages: 1088-1101
  • Peer Reviewed / Open Access
• [Journal Article] A tutorial to identify nonlinear associations in gene expression time series data (2014)
  • Author(s): Fujita A, Miyano S
  • Journal Title: Methods Mol Biol. Volume: 1164 Pages: 87-95
  • Peer Reviewed / Open Access
• [Journal Article] Landscape of genetic lesions in 944 patients with myelodysplastic syndromes (2014)
  • Author(s): Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S
  • Journal Title: Leukemia Volume: 28(2) Pages: 241-247
  • Peer Reviewed / Open Access
• [Journal Article] An efficient data assimilation schema for restoration and extension of gene regulatory networks using time-course observation data (2014)
  • Author(s): Hasegawa T, Mori T, Yamaguchi R, Imoto S, Miyano S, Akutsu T
  • Journal Title: J Comput Biol Volume: 21(11) Pages: 785-798
  • Peer Reviewed / Open Access
• [Journal Article] An efficient method of exploring simulation models by assimilating literature and biological observational data (2014)
  • Author(s): Hasegawa T, Nagasaki M, Yamaguchi R, Imoto S, Miyano S
  • Journal Title: Biosystems Volume: 121 Pages: 54-66
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent genetic defects on chromosome 7q in myeloid neoplasms (2014)
  • Author(s): Hosono N, Makishima H, Jerez A, Yoshida K, Przychodzen B, McMahon S, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Sanada M, Gomez-Segui I, Verma AK, McDevitt MA, Sekeres MA, Ogawa S, Maciejewski JP
  • Journal Title: Leukemia Volume: 28(6) Pages: 1348-1351
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients (2014)
  • Author(s): Kihara R, Nagata Y, Kiyoi H, Kato T, Yamamoto E, Suzuki K, Chen F, Asou N, Ohtake S, Miyawaki S, Miyazaki Y, Sakura T, Ozawa Y, Usui N, Kanamori H, Kiguchi T, Imai K, Uike N, et. al.
  • Journal Title: Leukemia Volume: 28(8) Pages: 1586-1595
  • Peer Reviewed / Open Access
• [Journal Article] CSML2SBML: a novel tool for converting quantitative biological pathway models from CSML into SBML (2014)
  • Author(s): Li C, Nagasaki M, Ikeda E, Sekiya Y, Miyano S
  • Journal Title: Biosystems Volume: 121 Pages: 22-28
  • Peer Reviewed / Open Access
• [Journal Article] Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations (2014)
  • Author(s): Lin TL, Nagata Y, Kao HW, Sanada M, Okuno Y, Huang CF, Liang DC, Kuo MC, Lai CL, Lee EH, Shih YS, Tanaka H, Shiraishi Y, Chiba K, Lin TH, Wu JH, Miyano S, Ogawa S, Shih LY
  • Journal Title: Haematologica Volume: 99(1) Pages: 28-36
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia (2014)
  • Author(s): Matsunawa M, Yamamoto R, Sanada M, Sato-Otsubo A, Shiozawa Y, Yoshida K, Otsu M, Shiraishi Y, Miyano S, Isono K, Koseki H, Nakauchi H, Ogawa S
  • Journal Title: Leukemia Volume: 28(9) Pages: 1844-1850
  • Peer Reviewed / Open Access
• [Journal Article] Robust prediction of anti-cancer drug sensitivity and sensitivity-specific biomarker (2014)
  • Author(s): Park H, Shimamura T, Miyano S, Imoto S
  • Journal Title: PLoS One Volume: 9(1) Pages: e108990
  • Peer Reviewed / Open Access
• [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma (2014)
  • Author(s): Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, Muto H, Tsuyama N, Sato-Otsubo A, Okuno Y, Sakata S, Kamada Y, Nakamoto-Matsubara R, et. al.
  • Journal Title: Nat Genet. Volume: 46(2) Pages: 171-175
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome (2014)
  • Author(s): Sato Y, Maekawa S, Ishii R, Sanada M, Morikawa T, Shiraishi Y, Yoshida K, Nagata Y, Sato-Otsubo A, Yoshizato T, Suzuki H, Shiozawa Y, Kataoka K, Kon A, Aoki K, Chiba K, Tanaka H, Kume H, Miyano S, Fukayama M, Nureki O, Homma Y, Ogawa S
  • Journal Title: Science Volume: 344(6186) Pages: 917-920
  • Peer Reviewed / Open Access
• [Journal Article] Loss of CDCP1 expression promotes invasiveness and poor prognosis in esophageal squamous cell carcinoma (2014)
  • Author(s): Sawada G, Takahashi Y, Niida A, Shimamura T, Kurashige J, Matsumura T, Ueo H, Uchi R, Takano Y, Ueda M, Hirata H, Sakimura S, Shinden Y, Eguchi H, Sudo T, Sugimachi K, Miyano S, Doki Y, Mori M, Mimori K
  • Journal Title: Ann Surg Oncol Volume: 21 Suppl 4 Pages: 640-647
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma (2014)
  • Author(s): Seki M, Yoshida K, Shiraishi Y, Shimamura T, Sato Y, Nishimura R, Okuno Y, Chiba K, Tanaka H, Kato K, Kato M, Hanada R, Nomura Y, Park MJ, Ishida T, Oka A, Igarashi T, Miyano S, Hayashi Y, Ogawa S, Takita J
  • Journal Title: Cancer Res. Volume: 74（１０） Pages: 2742-2749
  • Peer Reviewed / Open Access
• [Journal Article] A feature selection method using fixed-point algorithm for DNA microarray gene expression data (2014)
  • Author(s): Sharma A, Paliwal KK, Imoto S, Miyano S, Sharma V, Ananthanarayanan R
  • Journal Title: International Journal of Knowledge Based and Intelligent Engineering Systems Volume: 18(1) Pages: 55-59
  • Peer Reviewed / Open Access
• [Journal Article] A feature selection method using improved regularized linear discriminant analysis (2014)
  • Author(s): Sharma A, Paliwal KK, Imoto S, Miyano S
  • Journal Title: Mach Vis Appl. Volume: 25(3) Pages: 775-786
  • Peer Reviewed / Open Access
• [Journal Article] Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria (2014)
  • Author(s): Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T, Shiraishi Y, Miyano S, Ogawa S, Maciejewski JP, Makishima H
  • Journal Title: J Clin Invest Volume: 124(10) Pages: 4529-4538
  • Peer Reviewed / Open Access
• [Journal Article] Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers (2014)
  • Author(s): Shiraishi Y, Fujimoto A, Furuta M, Tanaka H, Chiba K, Boroevich KA, Abe T, Kawakami Y, Ueno M, Gotoh K, Ariizumi S, Shibuya T, Nakano K, Sasaki A, Maejima K, Kitada R, Hayami S, Shigekawa Y, Marubashi S, Yamada T, Kubo M, et. al.
  • Journal Title: PLoS One Volume: 9(12) Pages: e114263
  • Peer Reviewed / Open Access
• [Journal Article] Allelic Imbalance at an 8q24 Oncogenic SNP is involved in activating MYC in human colorectal cancer (2014)
  • Author(s): Sugimachi K, Niida A, Yamamoto K, Shimamura T, Imoto S, Iinuma H, Shinden Y, Eguchi H, Sudo T, Watanabe M, Tanaka J, Kudo S, Hase K, Kusunoki M, Yamada K, Shimada Y, Sugihara K, Maehara Y, Miyano S, Mori M, Mimori K
  • Journal Title: Ann Surg Oncol Volume: 21 Suppl 4 Pages: 515-521
  • Peer Reviewed / Open Access
• [Journal Article] The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC (2014)
  • Author(s): Takahashi Y, Sheridan P, Niida A, Sawada G, Uchi R, Mizuno H, Kurashige J, Sugimachi K, Sasaki S, Shimada Y, Hase K, Kusunoki M, Kudo S, Watanabe M, Yamada K, Sugihara K, Yamamoto H, Suzuki A, Doki Y, Miyano S, Mori M, Mimori K
  • Journal Title: Ann Oncol. Volume: 26(5) Pages: 935-942
  • Peer Reviewed / Open Access
• [Journal Article] Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma (2014)
  • Author(s): Totoki Y, Yoshida A, Hosoda F, Nakamura H, Hama N, Ogura K, Yoshida A, Fujiwara T, Arai Y, Toguchida J, Tsuda H, Miyano S, Kawai A, Shibata T
  • Journal Title: Genome Res Volume: 24(9) Pages: 1411-1420
  • Peer Reviewed / Open Access
• [Journal Article] HapMuC: somatic mutation calling using heterozygous germline variants near candidate mutations (2014)
  • Author(s): Usuyama N, Shiraishi Y, Sato Y, Kume H, Homma Y, Ogawa S, Miyano S, Imoto S
  • Journal Title: Bioinformatics Volume: 30(23) Pages: 3302-3309
  • Peer Reviewed / Open Access
• [Presentation] スーパーコンピュータによる薬物標的、疾病応答遺伝子の探索 (2015)
  • Author(s): 宮野 悟
  • Organizer: 医薬ライセンシング協会第 239回月例会
  • Place of Presentation: 学士会館(東京都千代田区)
  • Year and Date: 2015-03-18
  • Invited
• [Presentation] Understanding Cancer Heterogeneity with Supercomputers (2015)
  • Author(s): Satoru Miyano
  • Organizer: The Third BMIRC International Symposium
  • Place of Presentation: 池のおく園(福岡県田川市)
  • Year and Date: 2015-03-05
  • Invited
• [Presentation] Identification of Oncogenic Co-regulators using Infinite Relational Models (2014)
  • Author(s): Yoichi Chikahara, Atsushi Niida, Rui Yamaguchi, Seiya Imoto, Satoru Miyano
  • Organizer: The 15th International Conference on Systems Biology (ICSB) 2014
  • Place of Presentation: メルボルン(オーストラリア)
  • Year and Date: 2014-09-14 – 2014-09-18
• [Presentation] Supercomputers for Cancer Research and Cancer Big Data (2014)
  • Author(s): Satoru Miyano
  • Organizer: The 3rd SNU International Bioinformatics Workshop 2014
  • Place of Presentation: ソウル(韓国)
  • Year and Date: 2014-06-23
  • Invited
• [Presentation] バイオインフォマティクスとシステム生物学によるバイオマーカー探索 (2014)
  • Author(s): 宮野 悟
  • Organizer: 第21回HAB研究機構学術年会
  • Place of Presentation: 昭和大学(東京都品川区)
  • Year and Date: 2014-05-17
  • Invited