Annual Report 2017
Division of Translational Genomics (Kashiwa Campus)
Katsuya Tsuchihara, Hideki Makinoshima, Sachiyo Mimaki, Ayako Suzuki, Atsushi Yagishita, Rumi Fujioka, Hiroko Kumakura, Megumi Iwakura, Hitomi Okazaki, Ayame Takeda, Keita Saito, Junyan Du, Hiroyasu Esumi, Yutaka Suzuki, Shin Kawano, Tatsunosuke Ikemura, Keita Masuzawa,
Introduction
The Division of Translational Genomics closely collaborates with intramural and extramural basic and clinical researchers to develop novel anti-cancer therapeutics as well as to prove their concepts. Our division has been developing genome biomarker diagnostics, exploring rational molecular targets for anti-cancer therapies, and elucidating molecular mechanisms of oncogenesis, tumor progression, and therapeutic responses. Our division is managing a data center called SCRUM-Japan, a nation-wide cancer genome screening project for developing new anti-cancer drugs.
Our team and what we do
Weekly conferences for the whole division and individual research groups are held. As a SCRUM-Japan steering committee member, our division contributed to quarterly held committee meetings and ad hoc database working group meetings.
Research activities
A novel mechanism that lung cancer cells amplifies the wild type EGFR gene in a allele-specific manner under the stress of the third generation mutant-specific EGFR inhibitors was reported using cell culture models. Rapid and reasonable analysis of long DNA fragments more than 1 Kb length in lung cancer cells was performed and allele-specific gene alterations contributing to drug-resistance or gene expression were identified. Metabolic determinants of sensitivity to PI3K pathway inhibitor in small cell lung cancer were identified in their energy and nucleotide metabolic pathways. Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR antibody treatment in patients with colorectal cancer was reported. The study was conducted in an academia-industrial collaborating multi-center clinical research named the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study. SCRUM-Japan data center has been integrating clinical and genome analysis data of more than 9,600 cases and distributing these data to researchers at collaborating academic institutes and pharmaceutical companies.
Clinical trials
Screening project for Individualized Medicine in Japan (SCRUM-Japan): Data center
Education
Our division accepted and trained the following trainees: Graduate students from the University of Tokyo, staff physicians and residents of the National Cancer Center Hospital East and Keio University.
Future prospects
Conquering drug resistance of tumors treated with molecular target drugs is indispensable to improve the prognosis of patients with advanced solid tumors. Our division will have been engaging in the research to identify molecular mechanisms of drug resistance using multi-omics data of clinical samples and model systems. These results will be shared with academic and industrial researchers to enhance precision oncology.
List of papers published in January 2017 - March 2018
Journal
1. Yoshino T, Uetake H, Tsuchihara K, Shitara K, Yamazaki K, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Yamanaka K, Iwasaki K, Soeda J, Hihara M, Yamanaka T, Ochiai A, Muro K. Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naive Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. Clin Colorectal Cancer, 16:158-163, 2017
2. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, Nogami N, Matsumoto S, Kohno T, Tsuta K, Tsuchihara K, Ishii G, Nomura S, Sato A, Ohtsu A, Ohe Y, Goto K. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med, 5:42-50, 2017
3. Miyoshi T, Umemura S, Matsumura Y, Mimaki S, Tada S, Makinoshima H, Ishii G, Udagawa H, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Aokage K, Hishida T, Yoshida J, Nagai K, Goto K, Tsuboi M, Tsuchihara K. Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung. Clinical cancer research, 23:757-765, 2017
4. Ichikawa T, Saruwatari K, Mimaki S, Sugano M, Aokage K, Kojima M, Hishida T, Fujii S, Yoshida J, Kuwata T, Ochiai A, Suzuki K, Tsuboi M, Goto K, Tsuchihara K, Ishii G. Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia. Lung Cancer, 113:134-139, 2017
5. Suzuki A, Suzuki M, Mizushima-Sugano J, Frith MC, Makalowski W, Kohno T, Sugano S, Tsuchihara K, Suzuki Y. Sequencing and phasing cancer mutations in lung cancers using a long-read portable sequencer. DNA Res, 24:585-596, 2017
6. Hojo H, Dohmae T, Hotta K, Kohno R, Motegi A, Yagishita A, Makinoshima H, Tsuchihara K, Akimoto T. Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread out Bragg peak. Radiat Oncol, 12:111, 2017
7. Yagishita A, Ueno T, Esumi H, Saya H, Kaneko K, Tsuchihara K, Urano Y. Development of Highly Selective Fluorescent Probe Enabling Flow-Cytometric Isolation of ALDH3A1-Positive Viable Cells. Bioconjug Chem, 28:302-306, 2017
8. Takahashi T, Elzawahry A, Mimaki S, Furukawa E, Nakatsuka R, Nakamura H, Nishigaki T, Serada S, Naka T, Hirota S, Shibata T, Tsuchihara K, Nishida T, Kato M. Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. Genes Chromosomes Cancer, 56:303-313, 2017
9. Sekimoto N, Suzuki A, Suzuki Y, Sugano S. Expression of miR26a exhibits a negative correlation with HMGA1 and regulates cancer progression by targeting HMGA1 in lung adenocarcinoma cells. Mol Med Rep, 15:534-542, 2017
10. Shinozaki E, Yoshino T, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shitara K, Bando H, Mimaki S, Nakai C, Matsushima K, Suzuki Y, Akagi K, Yamanaka T, Nomura S, Fujii S, Esumi H, Sugiyama M, Nishida N, Mizokami M, Koh Y, Abe Y, Ohtsu A, Tsuchihara K. Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study. Br J Cancer, 117:1450-1458, 2017
11. Nukaga S, Yasuda H, Tsuchihara K, Hamamoto J, Masuzawa K, Kawada I, Naoki K, Matsumoto S, Mimaki S, Ikemura S, Goto K, Betsuyaku T, Soejima K. Amplification of EGFR Wild-Type Alleles in Non-Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors. Cancer Res, 77:2078-2089, 2017
12. Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, Goto K. A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nat Commun, 9:625, 2018
13. Sereewattanawoot S, Suzuki A, Seki M, Sakamoto Y, Kohno T, Sugano S, Tsuchihara K, Suzuki Y. Identification of potential regulatory mutations using multi-omics analysis and haplotyping of lung adenocarcinoma cell lines. Sci Rep, 8:4926, 2018