Annual Report 2018

Division of Genome Biology

Takashi Kohno, Kouya Shiraishi, Hideaki Ogiwara, Takashi Nakaoku, Yoko Shimada, Mariko Sasaki, Ayako Otsuka, Maiko Matsuda, Takayuki Honda, Takafumi Kuroda, Sou Hirose, Kazushi Yoshida, Junya Tabata, Tomoko Watanabe, Miyu Yoshida, Yoshie Iga

Introduction

 Clarification of somatic mutation profiles in the cancer genome and innate genetic variations are crucial to improve cancer genome medicine. Our division aims to find "seeds" that are translatable as part of work to develop novel methods for treating, diagnosing and preventing cancer.

The Team and What We Do

 We are working together with NCC staff from hospitals, EPOC and the Center for Public Health Sciences to fight cancers prevalent in Asian countries.

Research activities

 RET, which encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor, is an active driver oncogene in various human cancers. Fusion of RET with several partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic and breast cancers, against which tyrosine kinase inhibitors for RET show promising therapeutic effects. Oncogenic mutations within the extracellular cysteine-rich and intracellular kinase domains of RET drive medullary thyroid carcinogenesis; the same mutations as well as many variants of unknown significance are also observed in diverse other cancers. To conduct precision medicine for such cancers, we annotate RET mutants using a supercomputer-based molecular dynamics simulation coupled with in vitro experiments.

 ARID1A, a subunit of SWI/SNF chromatin remodeling complex, is frequently deficient in several cancers prevalent in Asian countries, such as ovarian clear cell carcinoma and cholangiocarcinoma and there is no effective molecular therapy targeting the deficiency. We showed how ARID1A-deficient cancer cells have a common feature of low SLC7A11 expression caused by impaired ARID1Amediated transcriptional activation. Such ARID1A-deficient cancer cells were specifically vulnerable to inhibitors of the glutathione (GSH) metabolic pathway, such as APR-246 for GSH and buthionine sulfoximine for GCLC, due to the low supply of cysteine, a key source of antioxidant GSH. Therefore, GCLC-targeting therapy is promising for ovarian and other cancers deficient in ARID1A (Figure 1).

 Risk factors for lung adenocarcinoma (LADC) are being sought by a multi-center collaborative genome-wide association study of SNPs. In addition, focusing on usual interstitial pneumonia (UIP), a strong risk factor for lung carcinogenesis, we clarified that UIP-positive LADCs develop through accumulated mutations caused by smoking. Pulmonary surfactant system genes were identified as targets for mutations and the mutations were associated with shorter overall survival of UIP-positive LADC patients. To understand the mutational and/or genetic features of cancers developed in adolescents and young adults (AYA; 15-39 years old), genomewide mutational analyses are conducted for ovarian and breast cancers.

Figure 1. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers

Clinical trials

 Cases involved in clinical trials, which investigate the therapeutic effect of RET-tyrosine kinase inhibitors, such as vandetanib, are subject to our study to understand and overcome acquired drug resistance.

Education

 Supervising research and presentation skills for graduate school students and young researchers.

Future prospects

 Our division aims to establish novel strategies for cancer genome medicine by finding unique "seeds". Understanding their hereditary and biological roles will provide unique and novel concepts to improve cancer therapy and prevention and help cancer genome medicine progress.

List of papers published in 2018

Journal

 1. Ikemura S, Yasuda H, Matsumoto S, Kamada M, Hamamoto J, Masuzawa K, Kobayashi K, Manabe T, Arai D, Nakachi I, Kawada I, Ishioka K, Nakamura M, Namkoong H, Naoki K, Ono F, Araki M, Kanada R, Ma B, Hayashi Y, Mimaki S, Yoh K, Kobayashi SS, Kohno T, Okuno Y, Goto K, Tsuchihara K, Soejima K. Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations. Proc Natl Acad Sci U S A, 116:10025-10030, 2019

 2. Wirth LJ, Kohno T, Udagawa H, Ishii G, Ebata KB, Tuch B, Zhu EY, Nguyen M, Smith S, Hanson LM, Burkhard MR, Cable L, Blake JF, Condroski KR, Brandhuber BJ, Andrews S, Rothenberg SM, Goto K. Emergence and targeting of acquired and hereditary resistance to multikinase RET inhibition in RET-altered cancer patients. JCO Prec Oncol, 2019

 3. Asano N, Matsuzaki J, Ichikawa M, Kawauchi J, Takizawa S, Aoki Y, Sakamoto H, Yoshida A, Kobayashi E, Tanzawa Y, Nakayama R, Morioka H, Matsumoto M, Nakamura M, Kondo T, Kato K, Tsuchiya N, Kawai A, Ochiya T. A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes. Nat Commun, 10:1299, 2019

 4. Sunami K, Ichikawa H, Kubo T, Kato M, Fujiwara Y, Shimomura A, Koyama T, Kakishima H, Kitami M, Matsushita H, Furukawa E, Narushima D, Nagai M, Taniguchi H, Motoi N, Sekine S, Maeshima A, Mori T, Watanabe R, Yoshida M, Yoshida A, Yoshida H, Satomi K, Sukeda A, Hashimoto T, Shimizu T, Iwasa S, Yonemori K, Kato K, Morizane C, Ogawa C, Tanabe N, Sugano K, Hiraoka N, Tamura K, Yoshida T, Fujiwara Y, Ochiai A, Yamamoto N, Kohno T. Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study. Cancer Sci, 110:1480-1490, 2019

 5. Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima H, Chiwaki F, Sasaki H, Kato T, Okamoto A, Kohno T. Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers. Cancer Cell, 35:177-190.e8, 2019

 6. Seki M, Katsumata E, Suzuki A, Sereewattanawoot S, Sakamoto Y, Mizushima-Sugano J, Sugano S, Kohno T, Frith MC, Tsuchihara K, Suzuki Y. Evaluation and application of RNA-Seq by MinION. DNA Res, 26:55-65, 2019

 7. Uchida S, Tsuta K, Kusumoto M, Shiraishi K, Kohno T, Watanabe SI. Radiopathologic correlation of collision lung cancer with ground-glass opacity. Asian Cardiovasc Thorac Ann, 27:45-48, 2019

 8. Fujiwara Y, Saito M, Robles AI, Nishida M, Takeshita F, Watanabe M, Ochiya T, Yokota J, Kohno T, Harris CC, Tsuchiya N. A Nucleolar Stress-Specific p53-miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor Network. EBioMedicine, 33:33-48, 2018

 9. Seki Y, Fujiwara Y, Kohno T, Yoshida K, Goto Y, Horinouchi H, Kanda S, Nokihara H, Yamamoto N, Kuwano K, Ohe Y. Circulating cell-free plasma tumour DNA shows a higher incidence of EGFR mutations in patients with extrathoracic disease progression. ESMO Open, 3:e000292, 2018

10. 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

11. Kohno T. Implementation of "clinical sequencing" in cancer genome medicine in Japan. Cancer Sci, 109:507-512, 2018

12. Honda T, Sakashita H, Masai K, Totsuka H, Motoi N, Kobayashi M, Akashi T, Mimaki S, Tsuchihara K, Chiku S, Shiraishi K, Shimada Y, Otsuka A, Kanai Y, Okubo K, Watanabe S, Tsuta K, Inase N, Kohno T. Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia. JCO Prec Oncol, 2018

13. Saito M, Saito K, Shiraishi K, Maeda D, Suzuki H, Minamiya Y, Kono K, Kohno T, Goto A. Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer. Mol Clin Oncol, 8:310-314, 2018

14. Saito M, Suzuki H, Kono K, Takenoshita S, Kohno T. Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy. Surg Today, 48:1-8, 2018

15. Saito M, Shiraishi K, Goto A, Suzuki H, Kohno T, Kono K. Development of targeted therapy and immunotherapy for treatment of small cell lung cancer. Jpn J Clin Oncol, 48:603-608, 2018