Annual Report 2019
Division of Genome Biology
Takashi Kohno, Kouya Shiraishi, Takashi Nakaoku, Yoko Shimada, Ayako Otsuka, Maiko Matsuda, Kuniko Sunami, Takafumi Kuroda, Junya Tabata, Tomoko Watanabe, Yoshie Iga, Tomoka Asami, Saisuke Takayanagi, Tsuyuka Otsuki, Takaaki Mizuno
Introduction
Clarification of somatic mutation profiles in the cancer genome and innate genetic variations are a crucial key to improve cancer genome medicine. Our division aims to find “seeds” that are translatable to the development of novel methods for the treatment, diagnosis and prevention of cancer.
The Team and What We Do
We are working together with the NCC staff from hospitals, EPOC and the Center for Public Health Sciences to fight cancers prevalent in Asian countries.
Research activities
RET fusion, a druggable target discovered by us, sometimes acquires secondary resistant mutation against molecular target therapy using RET tyrosine kinase inhibitors (TKIs). We showed in a clinical trial that a novel RET-specific TKI, selpercatinib/loxo-292, overcomes such resistant mutation. Most mutations of the RET gene observed in thyroid, lung, colorectal, pancreatic, breast and gynecologic cancers are classified as variants of unknown significance (VUS). To annotate such VUS in RET, representative RET mutants are being annotated by molecular dynamics (MD) simulation coupled with in vitro experiments (Figure). ROS1 fusion was defined as a therapeutic target for pleomorphic lung cancer.
Figure. Variants of unknown significance (VUS) in the RET gene
Real-world data obtained from medical records of patients gives us real world evidence. Data analysis of LC-SCRUM-Japan, a pan-Japan mutation screening system for lung cancer, revealed that >90% of lung cancers with rare EGFR mutations are subject to 1st line treatment of EGFR TKIs. We showed that the efficacy of osimertinib, an EGFR-TKI, for such rare EGFR mutants can be deduced by MD simulation. Analysis of medical records of National Cancer and Jikei University Hospitals revealed that a subset of ovarian clear cell carcinomas responds to gemcitabine associated with ARID1A deficiency.
To understand mutational and/or genetic features of cancers that developed in adolescents and young adults (AYA; 15-39 years old), genome-wide mutational analyses were conducted for gynecologic and colorectal cancers. Genome profiling of uterine cervical cancers revealed actionable/druggable alterations and a prognosis biomarker, STK11. Risk and prognosis factors for lung cancer were discovered by international lung cancer studies.
Clinical trials
Cases involved in clinical trials, which investigate the therapeutic effect of RET-TKI, such as selpercatinib, are subject to our study to understand and overcome acquired drug resistance.
Education
Supervising the 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 novel therapeutic and diagnostic “seeds”. Understanding their hereditary and biological roles will provide unique and novel concepts for improving cancer therapy and prevention, and help cancer genome medicine progress.
List of papers published in 2019
Journal
1. Sasaki M, Chiwaki F, Kuroda T, Komatsu M, Matsusaki K, Kohno T, Sasaki H, Ogiwara H. Efficacy of glutathione inhibitors for the treatment of ARID1A-deficient diffuse-type gastric cancers. Biochem Biophys Res Commun, 522:342-347, 2020
2. Wong JYY, Zhang H, Hsiung CA, Shiraishi K, Yu K, Matsuo K, Wong MP, Hong YC, Wang J, Seow WJ, Wang Z, Song M, Kim HN, Chang IS, Chatterjee N, Hu W, Wu C, Mitsudomi T, Zheng W, Kim JH, Seow A, Caporaso NE, Shin MH, Chung LP, An SJ, Wang P, Yang Y, Zheng H, Yatabe Y, Zhang XC, Kim YT, Cai Q, Yin Z, Kim YC, Bassig BA, Chang J, Ho JCM, Ji BT, Daigo Y, Ito H, Momozawa Y, Ashikawa K, Kamatani Y, Honda T, Hosgood HD, Sakamoto H, Kunitoh H, Tsuta K, Watanabe SI, Kubo M, Miyagi Y, Nakayama H, Matsumoto S, Tsuboi M, Goto K, Shi J, Song L, Hua X, Takahashi A, Goto A, Minamiya Y, Shimizu K, Tanaka K, Wei F, Matsuda F, Su J, Kim YH, Oh IJ, Song F, Su WC, Chen YM, Chang GC, Chen KY, Huang MS, Chien LH, Xiang YB, Park JY, Kweon SS, Chen CJ, Lee KM, Blechter B, Li H, Gao YT, Qian B, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Tsai YH, Jung YJ, Guo H, Hu Z, Wang WC, Chung CC, Burdett L, Yeager M, Hutchinson A, Berndt SI, Wu W, Pang H, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Zhu M, Chen CH, Yang TY, Xu J, Guan P, Tan W, Wang CL, Hsin M, Sit KY, Ho J, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Lin CC, Park IK, Xu P, Wang Y, He Q, Perng RP, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Li YJ, Li J, Chen H, Yu CJ, Jin L, Chen TY, Jiang SS, Liu J, Yamaji T, Hicks B, Wyatt K, Li SA, Dai J, Ma H, Jin G, Song B, Wang Z, Cheng S, Li X, Ren Y, Cui P, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Chen Y, Yang K, Jiang G, Fei K, Wu G, Lin HC, Chen HL, Fang YH, Tsai FY, Hsieh WS, Yu J, Stevens VL, Laird-Offringa IA, Marconett CN, Rieswijk L, Chao A, Yang PC, Shu XO, Wu T, Wu YL, Lin D, Chen K, Zhou B, Huang YC, Kohno T, Shen H, Chanock SJ, Rothman N, Lan Q. Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women. Genomics, 112:1223-1232, 2020
3. Hirose S, Murakami N, Takahashi K, Kuno I, Takayanagi D, Asami Y, Matsuda M, Shimada Y, Yamano S, Sunami K, Yoshida K, Honda T, Nakahara T, Watanabe T, Komatsu M, Hamamoto R, Kato MK, Matsumoto K, Okuma K, Kuroda T, Okamoto A, Itami J, Kohno T, Kato T, Shiraishi K, Yoshida H. Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients. Gynecol Oncol, 156:203-210, 2020
4. Kuroda T, Kohno T. Precision medicine for ovarian clear cell carcinoma based on gene alterations. Int J Clin Oncol, 25:419-424, 2020
5. Kuroda T, Ogiwara H, Sasaki M, Takahashi K, Yoshida H, Kiyokawa T, Sudo K, Tamura K, Kato T, Okamoto A, Kohno T. Therapeutic preferability of gemcitabine for ARID1A-deficient ovarian clear cell carcinoma. Gynecol Oncol, 155:489-498, 2019
6. 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, DOI:10.1200/PO.19.00189, 2019
7. 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
8. 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
9. Shepshelovich D, Xu W, Lu L, Fares A, Yang P, Christiani D, Zhang J, Shiraishi K, Ryan BM, Chen C, Schwartz AG, Tardon A, Wu X, Schabath MB, Teare MD, Le Marchand L, Zhang ZF, Field JK, Brenner H, Diao N, Xie J, Kohno T, Harris CC, Wenzlaff AS, Fernandez-Tardon G, Ye Y, Taylor F, Wilkens LR, Davies M, Liu Y, Barnett MJ, Goodman GE, Morgenstern H, Holleczek B, Brown MC, Liu G, Hung RJ. Body Mass Index (BMI), BMI Change, and Overall Survival in Patients With SCLC and NSCLC: A Pooled Analysis of the International Lung Cancer Consortium. J Thorac Oncol, 14:1594-1607, 2019
10. Udagawa C, Horinouchi H, Shiraishi K, Kohno T, Okusaka T, Ueno H, Tamura K, Ohe Y, Zembutsu H. Whole genome sequencing to identify predictive markers for the risk of drug-induced interstitial lung disease. PLoS One, 14:e0223371, 2019
11. Suzuki A, Onodera K, Matsui K, Seki M, Esumi H, Soga T, Sugano S, Kohno T, Suzuki Y, Tsuchihara K. Characterization of cancer omics and drug perturbations in panels of lung cancer cells. Sci Rep, 9:19529, 2019
12. Mizuno T, Fujiwara Y, Yoshida K, Kohno T, Ohe Y. Next-Generation Sequencer Analysis of Pulmonary Pleomorphic Carcinoma With a CD74-ROS1 Fusion Successfully Treated With Crizotinib. J Thorac Oncol, 14:e106-e108, 2019
13. Tsukada T, Yoshida H, Ishikawa M, Asami Y, Shiraishi K, Kato T. Malignant struma ovarii presenting with follicular carcinoma: A case report with molecular analysis. Gynecol Oncol Rep, 30:100498, 2019
14. Kojima N, Yoshida H, Uehara T, Ushigusa T, Asami Y, Shiraishi K, Kato T. Primary Clear Cell Adenocarcinoma of the Vulva: A Case Study With Mutation Analysis and Literature Review. Int J Surg Pathol, 27:792-797, 2019
15. 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