Annual Report 2021
Division of Genome Biology
Takashi Kohno, Kouya Shiraishi, Takashi Nakaoku, Kuniko Sunami, Shu Yazaki, Makoto Nishino, Masayuki Shirasawa, Junya Tabata, Tomoka Asami, Takaaki Mizuno, Kosuke Maruyama, Kengo Hiranuma, Shigenari Nukaga, Ryoko Higashiyama, Atsushi Kawamura, Hourin Cho, Erika Machida, Akihumi Mochizuki, Yoko Shimada, Ayaka Otsuka, Maiko Matsuda, Yoshie Iga, Megumi Ishigami, Kazumi Uchiyama, Keiko Miyoshi, Mitsuo Kiyono, Yuki Sanada, Ayako Ui
Introduction
The goal of our research is to understand the genomic information of cancer cells and tissues as well as cancer patients and to understand their biological significance in order to elucidate the characteristics and properties of cancer and to identify and put into practice the seeds of cancer prevention, diagnosis, and treatment targets that will contribute to personalized medicine. The research is being conducted in collaboration with the staff of our center's hospital and other institutions.
The Team and What We Do
The research is being conducted in collaboration with the staff of our center's hospital and other institutions.
Research activities
In collaboration with LC-SCRUM-Japan and a pharmaceutical company, we supported the implementation of Selpercatinib/Retevmo™, a RET-specific inhibitor for RET fusion-positive lung cancer, which was approved by the PMDA in September 2021 and included in the insurance coverage in December (Figure 1). On the other hand, since more than 90% of RET mutations in various cancers are of unknown significance (VUS), we conducted biochemical and biological experiments and molecular dynamics simulation studies to determine the significance of these mutations.
We initiated a project of whole genome sequencing analysis of lung cancer and started discussions on how to implement whole genome sequencing analysis in cancer genome medicine. We identified candidate variants of genetic factors that promote the development of AYA generation (15-39 years old) cancer and analyzed their associations with AYA cancer risks. We participated in multiple international lung cancer collaborations to search for genetic factors that define risks for lung cancer.
In collaboration with NCCH staff, we have identified genomic alterations in early-stage lung adenocarcinoma and the molecular profiles associated with the efficacy of immune checkpoint inhibitor therapy. In conjunction with this work, we also revealed the relationship between genomic profiles of gynecological tumors such as cervical cancer, endometrial cancer, and ovarian cancer, and treatment efficacy and prognosis.
Clinical trials
Patients who participate in the clinical trials investigating the therapeutic efficacy of RET-specific inhibitors will be the focus of our research in understanding and overcoming acquired drug resistance.
Education
We have mentored graduate students and young researchers with their research and presentation skills.
Future Prospects
Genome analysis of lung cancer, gynecological cancer, and AYA cancer is expected to identify target molecules that will contribute to the development of new prevention, diagnosis, and treatment methods. We seek to contribute to promoting precision cancer medicine by linking this analysis with gene panel tests, which are covered by Japan's national insurance system.
List of papers published in 2021
Journal
1. Kobayashi Kato M, Asami Y, Takayanagi D, Matsuda M, Shimada Y, Hiranuma K, Kuno I, Komatsu M, Hamamoto R, Matsumoto K, Ishikawa M, Kohno T, Kato T, Shiraishi K, Yoshida H. Clinical impact of genetic alterations of CTNNB1 in patients with grade 3 endometrial endometrioid carcinoma. Cancer science, 113:1712-1721, 2022
2. Murakami N, Kuno I, Yoshida H, Shiraishi K, Kato T, Igaki H. How should we appropriately classify low-risk uterine cervical cancer patients suitable for de-intensified treatment? Journal of radiation research, 63:312-313, 2022
3. Zhang M, Kiyono T, Aoki K, Goshima N, Kobayashi S, Hiranuma K, Shiraishi K, Saya H, Nakahara T. Development of an in vitro carcinogenesis model of human papillomavirus-induced cervical adenocarcinoma. Cancer science, 113:904-915, 2022
4. Takayanagi D, Cho H, Machida E, Kawamura A, Takashima A, Wada S, Tsunoda T, Kohno T, Shiraishi K. Update on Epidemiology, Diagnosis, and Biomarkers in Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers, 14:2022
5. Schmid S, Jiang M, Brown MC, Fares A, Garcia M, Soriano J, Dong M, Thomas S, Kohno T, Leal LF, Diao N, Xie J, Wang Z, Zaridze D, Holcatova I, Lissowska J, świątkowska B, Mates D, Savic M, Wenzlaff AS, Harris CC, Caporaso NE, Ma H, Fernandez-Tardon G, Barnett MJ, Goodman G, Davies MPA, Pérez-Ríos M, Taylor F, Duell EJ, Schoettker B, Brenner H, Andrew A, Cox A, Ruano-Ravina A, Field JK, Marchand LL, Wang Y, Chen C, Tardon A, Shete S, Schabath MB, Shen H, Landi MT, Ryan BM, Schwartz AG, Qi L, Sakoda LC, Brennan P, Yang P, Zhang J, Christiani DC, Reis RM, Shiraishi K, Hung RJ, Xu W, Liu G . Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 31:679-687, 2022
6. Mizuno T, Yoshida T, Sunami K, Koyama T, Okita N, Kubo T, Sudo K, Shimoi T, Ueno H, Saito E, Katanoda K, Shibata T, Yonemori K, Okusaka T, Boku N, Ohe Y, Hiroshima Y, Ueno M, Kuboki Y, Doi T, Nakamura K, Kohno T, Yatabe Y, Yamamoto N. Study protocol for NCCH1908 (UPFRONT-trial): a prospective clinical trial to evaluate the feasibility and utility of comprehensive genomic profiling prior to the initial systemic treatment in advanced solid tumour patients. Japanese journal of clinical oncology, 51:1757-1760, 2021
7. Shirasawa M, Yoshida T, Shimoda Y, Takayanagi D, Shiraishi K, Kubo T, Mitani S, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Ichikawa H, Kohno T, Yamamoto N, Matsumoto S, Goto K, Watanabe SI, Ohe Y, Motoi N. Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 16:2078-2090, 2021
8. Yotsukura M, Asamura H, Motoi N, Kashima J, Yoshida Y, Nakagawa K, Shiraishi K, Kohno T, Yatabe Y, Watanabe SI. Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 16:1312-1320, 2021
9. Teishikata T, Shiraishi K, Shinno Y, Kobayashi Y, Kashima J, Ishiyama T, Yoshida T, Mori T, Yatabe Y. An Alert to Possible False Positives With a Commercial Assay for MET Exon 14 Skipping. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 16:2133-2138, 2021
10. Yoshida H, Asami Y, Kobayashi-Kato M, Tanase Y, Uno M, Ishikawa M, Shiraishi K, Kato T. Genetic features of endometrioid-type endometrial carcinoma arising in uterine adenomyosis. Virchows Archiv: an international journal of pathology, 2021
11. Yoshida H, Shiraishi K, Kato T. Molecular Pathology of Human Papilloma Virus-Negative Cervical Cancers. Cancers, 13:2021
12. Murakami N, Asami Y, Yoshida H, Takayanagi D, Hirose S, Kuno I, Takahashi K, Matsuda M, Shimada Y, Yamano S, Sunami K, Honda T, Nakahara T, Watanabe T, Okuma K, Kuroda T, Kohno T, Kato T, Shiraishi K, Itami J. Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy. Scientific reports, 11:10567, 2021
13. Kaneko S, Mitsuyama T, Shiraishi K, Ikawa N, Shozu K, Dozen A, Machino H, Asada K, Komatsu M, Kukita A, Sone K, Yoshida H, Motoi N, Hayami S, Yoneoka Y, Kato T, Kohno T, Natsume T, Keudell GV, Saloura V, Yamaue H, Hamamoto R. Genome-Wide Chromatin Analysis of FFPE Tissues Using a Dual-Arm Robot with Clinical Potential. Cancers, 13:2021
14. Kuno I, Takayanagi D, Asami Y, Murakami N, Matsuda M, Shimada Y, Hirose S, Kato MK, Komatsu M, Hamamoto R, Okuma K, Kohno T, Itami J, Yoshida H, Shiraishi K, Kato T. TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer. Scientific reports, 11:19261, 2021
15. Ishioka K, Yasuda H, Hamamoto J, Terai H, Emoto K, Kim TJ, Hirose S, Kamatani T, Mimaki S, Arai D, Ohgino K, Tani T, Masuzawa K, Manabe T, Shinozaki T, Mitsuishi A, Ebisudani T, Fukushima T, Ozaki M, Ikemura S, Kawada I, Naoki K, Nakamura M, Ohtsuka T, Asamura H, Tsuchihara K, Hayashi Y, Hegab AE, Kobayashi SS, Kohno T, Watanabe H, Ornitz DM, Betsuyaku T, Soejima K, Fukunaga K. Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer. Cancer research, 81:3916-3929, 2021
16. Takahashi K, Takenaka M, Okamoto A, Bowtell DDL, Kohno T. Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma. Cancers, 13:2021
17. Yiming R, Takeuchi Y, Nishimura T, Li M, Wang Y, Meguro-Horike M, Kohno T, Horike SI, Nakata A, Gotoh N. MUSASHI-2 confers resistance to third-generation EGFR-tyrosine kinase inhibitor osimertinib in lung adenocarcinoma. Cancer science, 112:3810-3821, 2021
18. Coll-SanMartin L, Davalos V, Piñeyro D, Rosselló-Tortella M, Bueno-Costa A, Setien F, Villanueva A, Granada I, Ruiz-Xiviller N, Kotter A, Helm M, Yokota J, Kawabata-Iwakawa R, Kohno T, Esteller M . Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer. Cancers, 13:2021
19. Yonemaru J, Hashimoto T, Takayanagi D, Naka T, Yatabe Y, Kanemitsu Y, Shiraishi K, Sekine S. NTRK fusion-positive colorectal cancer in Japanese population. Pathology international, 71:355-359, 2021
20. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, Nogami N, Nosaki K, Kohno T, Tsuta K, Nomura S, Ikeno T, Wakabayashi M, Sato A, Matsumoto S, Goto K. Final survival results for the LURET phase II study of vandetanib in previously treated patients with RET-rearranged advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 155:40-45, 2021