Annual Report 2020
Division of Genome Biology
Takashi Kohno, Kouya Shiraishi, Takashi Nakaoku, Kuniko Sunami, Yoko Shimada, Ayako Otsuka, Maiko Matsuda, Yoshie Iga, Kazumi Uchityama, Junya Tabata, Tomoka Asami, Daisuke Takayanagi, Tsuyuka Otsuki, Takaaki Mizuno, Kosuke Maruyama, Kengo HIranuma, Atsushi Kawamura, 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 our center's hospital staff and those of other institutions.
Research activities
The collaboration between LC-SCRUM-Japan and a pharmaceutical company has shown that Selpercatinib/Retevmo™ (LOXO-292), a novel RET-specific inhibitor, is highly effective in RET fusion-positive lung cancer. The drug was approved by the U.S. Food and Drug Administration (FDA) in May 2020 after demonstrating efficacy for more than one year and in 85% of first-line patients. Given that more than 90% of RET mutations occurring in various types of cancer are variants of unknown significance (VUS), we are conducting molecular dynamics simulation studies to determine the pathogenicity and therapeutic significance of VUS.
Based on the results of the NCC Oncopanel test, we found that maternal cervical cancer cells are transmitted through the amniotic fluid to the newborn's lungs at birth, causing pediatric lung cancer (Figure 1). We also found that cancer cells transmitted from the mother are highly responsive to immune checkpoint inhibition therapy. These results indicate that introducing cancer gene panel tests, such as the NCC Oncopanel, which we developed, into the medical field will enable the discovery of new cancer etiologies and the accurate understanding of its pathogenesis.
To elucidate the genetic factors that promote the development of cancer in AYA generation (15-39 years old), we performed whole genome sequencing analysis of the germline of AYA breast, gynecological and colorectal cancers and found that large-scale structural changes are responsible for inactivating cancer susceptibility genes. We also showed that long-read whole genome sequencing analysis is useful for identifying the complex structural changes occurring in lung cancer. We have participated in several international lung cancer research collaborations to identify the genetic factors that determine the prognosis of non-smoking lung cancer patients.
Clinical trials
Patients who participate in the clinical trials investigating the therapeutic efficacy of RET-specific inhibitors, such as selpercatinib, will be the focus of our research in understanding and overcoming acquired drug resistance.
Education
We have mentored graduate students and young researchers in 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 the promoting precision cancer medicine by linking it with gene panel tests, which are covered by Japan's national insurance system.
List of papers published in 2020
Journal
1. Arakawa A, Ichikawa H, Kubo T, Motoi N, Kumamoto T, Nakajima M, Yonemori K, Noguchi E, Sunami K, Shiraishi K, Kakishima H, Yoshida H, Hishiki T, Kawakubo N, Kuroda T, Kiyokawa T, Yamada K, Yanaihara N, Takahashi K, Okamoto A, Hirabayashi S, Hasegawa D, Manabe A, Ono K, Matsuoka M, Arai Y, Togashi Y, Shibata T, Nishikawa H, Aoki K, Yamamoto N, Kohno T, Ogawa C. Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. N Engl J Med, 384:42-50, 2021
2. Kase K, Saito M, Nakajima S, Takayanagi D, Saito K, Yamada L, Ashizawa M, Nakano H, Hanayama H, Onozawa H, Okayama H, Endo H, Fujita S, Sakamoto W, Saze Z, Momma T, Mimura K, Ohki S, Shiraishi K, Kohno T, Kono K. ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation. Carcinogenesis, 42:21-30, 2021
3. Hamada K, Tian Y, Fujimoto M, Takahashi Y, Kohno T, Tsuta K, Watanabe SI, Yoshida T, Asamura H, Kanai Y, Arai E. DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative'-type lung adenocarcinomas. Carcinogenesis, 42:169-179, 2021
4. Jiang M, Fares AF, Shepshelovich D, Yang P, Christiani D, Zhang J, Shiraishi K, Ryan BM, Chen C, Schwartz AG, Tardon A, Shete S, 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, Thomas S, Brown MC, Hung RJ, Xu W, Liu G. The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients. Lung Cancer, 152:58-65, 2021
5. Takayanagi D, Hirose S, Kuno I, Asami Y, Murakami N, Matsuda M, Shimada Y, Sunami K, Komatsu M, Hamamoto R, Kato MK, Matsumoto K, Kohno T, Kato T, Shiraishi K, Yoshida H. Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix. Cancers (Basel), 13:2021
6. Shirasawa M, Yoshida T, Takayanagi D, Shiraishi K, Yagishita S, Sekine K, Kanda S, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Hamada A, Kohno T, Yamamoto N, Watanabe SI, Ohe Y, Motoi N. Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma. Clin Lung Cancer, 2021
7. Kurashima K, Kashiwagi H, Shimomura I, Suzuki A, Takeshita F, Mazevet M, Harata M, Yamashita T, Yamamoto Y, Kohno T, Shiotani B. SMARCA4 deficiency-associated heterochromatin induces intrinsic DNA replication stress and susceptibility to ATR inhibition in lung adenocarcinoma. NAR Cancer, 2:zcaa005, 2020
8. Semba T, Sato R, Kasuga A, Suina K, Shibata T, Kohno T, Suzuki M, Saya H, Arima Y. Lung Adenocarcinoma Mouse Models Based on Orthotopic Transplantation of Syngeneic Tumor-Initiating Cells Expressing EpCAM, SCA-1, and Ly6d. Cancers (Basel), 12:2020
9. Watanabe T, Honda T, Totsuka H, Yoshida M, Tanioka M, Shiraishi K, Shimada Y, Arai E, Ushiama M, Tamura K, Yoshida T, Kanai Y, Kohno T. Simple prediction model for homologous recombination deficiency in breast cancers in adolescents and young adults. Breast Cancer Res Treat, 182:491-502, 2020
10. Sakamoto Y, Xu L, Seki M, Yokoyama TT, Kasahara M, Kashima Y, Ohashi A, Shimada Y, Motoi N, Tsuchihara K, Kobayashi SS, Kohno T, Shiraishi Y, Suzuki A, Suzuki Y. Long-read sequencing for non-small-cell lung cancer genomes. Genome Res, 30:1243-1257, 2020
11. Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Terao C, Amariuta T, Gazal S, Kochi Y, Horikoshi M, Suzuki K, Ito K, Koyama S, Ozaki K, Niida S, Sakata Y, Sakata Y, Kohno T, Shiraishi K, Momozawa Y, Hirata M, Matsuda K, Ikeda M, Iwata N, Ikegawa S, Kou I, Tanaka T, Nakagawa H, Suzuki A, Hirota T, Tamari M, Chayama K, Miki D, Mori M, Nagayama S, Daigo Y, Miki Y, Katagiri T, Ogawa O, Obara W, Ito H, Yoshida T, Imoto I, Takahashi T, Tanikawa C, Suzuki T, Sinozaki N, Minami S, Yamaguchi H, Asai S, Takahashi Y, Yamaji K, Takahashi K, Fujioka T, Takata R, Yanai H, Masumoto A, Koretsune Y, Kutsumi H, Higashiyama M, Murayama S, Minegishi N, Suzuki K, Tanno K, Shimizu A, Yamaji T, Iwasaki M, Sawada N, Uemura H, Tanaka K, Naito M, Sasaki M, Wakai K, Tsugane S, Yamamoto M, Yamamoto K, Murakami Y, Nakamura Y, Raychaudhuri S, Inazawa J, Yamauchi T, Kadowaki T, Kubo M, Kamatani Y. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet, 52:669-679, 2020
12. Brhane Y, Yang P, Christiani DC, Liu G, McLaughlin JR, Brennan P, Shete S, Field JK, Tardón A, Kohno T, Shiraishi K, Matsuo K, Bossé Y, Amos CI, Hung RJ. Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium. Cancer Epidemiol Biomarkers Prev, 29:1983-1992, 2020