Annual Report 2024

Division of Genome Biology

Takashi Kohno, Kouya Shiraishi, Takashi Nakaoku, Kuniko Sunami, Takashi Yugawa, Akiko Tateishi, Yukiko Igawa, Masahiro Torasawa, Tomoka Asami, Kosuke Maruyama, Shigenari Nukaga, Yu Hamaguchi, Ryoko Higashiyama, Akihumi Mochizuki, Michiko Ueki, Satoshi Endo, Taro Yamanaka, Takayuki Kawai, Rui Kitadai, Maiko Yamaguchi, Daiki Higuchi, Teruki Tsunashima, Megumi Ishigami, Yuri Yamauchi, Yoko Shimada, Kazumi Uchiyama, Emi Ogawa, Nguyen Thai Le, Ayako Ui, Masayuki Shirasawa, Erika Machida, Erisa Fujii, Hourin Cho

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 in order 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 hospitals and other institutions.

The Team and What We Do

 The research is being conducted in collaboration with the staff of our center's hospitals and other institutions.

Research Activities

 Whole-genome analyses were performed on lung cancer to explore somatic genetic alterations that serve as therapeutic targets, as well as potential risk factors. As a result, it was revealed that passive smoking induces mutations through mechanisms distinct from those of active smoking, promotes the malignant progression of cells harboring driver oncogene mutations, and contributes to the development of lung cancer (Figure 1). Furthermore, spatial transcriptomic analysis uncovered dynamic changes in the tumor microenvironment during the process of lung adenocarcinogenesis.

Figure 1. Mutations induced by passive smoking differ from those induced by active smoking

 An international collaborative study, the Female Lung Cancer Consortium in Asia (FLCCA), was conducted focusing on lung adenocarcinoma that developed in never-smoking women from East Asian regions, including Japan, Taiwan, China, Hong Kong, Singapore, and South Korea. The study revealed that the cumulative effect of individual genetic polymorphisms increases susceptibility to EGFR-mutated lung adenocarcinoma, which is commonly observed in Asians, by 8.6-fold (Figure 2).

Figure 2. EGFR-mutated lung adenocarcinoma risk by polygenic risk score quartiles

Clinical Trials

 We conducted a prospective whole-genome sequencing project in collaboration with the staff of National Cancer Center Hospital (UMIN000011141).

Education

 We have mentored graduate students and young researchers with their research and presentation skills.

Future Prospects

 Omics analysis of lung and other cancers is expected to identify target molecules that will contribute to the development of new prevention, diagnosis, and treatment modalities. We seek to contribute to promoting precision cancer medicine by linking this analysis with a gene panel test (NCC Oncopanel), which is conducted under Japan's national health insurance system.

List of papers published in 2024

Journal

1. Blechter B, Hsiung CA, Wang X, Zhang H, Seow WJ, Shi J, Chatterjee N, Kim HN, Wong MP, Hong YC, Wong JYY, Dai J, Hosgood HD, Wang Z, Chang IS, Choi J, Wang J, Song M, Hu W, Zheng W, Kim JH, Zhou B, Albanes D, Shin MH, Chung LP, An SJ, Zheng H, Yatabe Y, Zhang XC, Kim YT, Shu XO, Kim YC, Vermeulen RCH, Bassig BA, Chang J, Man Ho JC, Ji BT, Kubo M, Daigo Y, Momozawa Y, Kamatani Y, Honda T, Kunitoh H, Watanabe SI, Miyagi Y, Nakayama H, Matsumoto S, Tsuboi M, Goto K, Yin Z, Takahashi A, Goto A, Minamiya Y, Shimizu K, Tanaka K, Wu T, Wei F, Su J, Kim YH, Oh IJ, Fun Lee VH, Su WC, Chen YM, Chang GC, Chen KY, Huang MS, Lin HC, Seow A, Park JY, Kweon SS, Chen CJ, Gao YT, Wu C, Qian B, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Tsai YH, Jung YJ, Guo H, Hu Z, Chen TY, Burdett L, Yeager M, Hutchinson A, Berndt SI, Wu W, Wang J, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Chen CH, Xu J, Guan P, Tan W, Wang CL, Loon Sihoe AD, Chen Y, Choi YY, Kim JS, Yoon HI, Cai Q, Park IK, Xu P, He Q, Chen CY, Wu J, Lim WY, Chen KC, Chan JKC, Li J, Chen H, Yu CJ, Jin L, Fraumeni JF Jr, Liu J, Landi MT, Yamaji T, Yang Y, Hicks B, Wyatt K, Li SA, Ma H, Song B, Wang Z, Cheng S, Li X, Ren Y, Iwasaki M, Zhu J, Jiang G, Fei K, Wu G, Chien LH, Tsai FY, Yu J, Stevens VL, Yang PC, Lin D, Chen K, Wu YL, Matsuo K, Rothman N, Shiraishi K, Shen H, Chanock SJ, Kohno T, Lan Q. Polygenic Risk Score and Lung Adenocarcinoma Risk Among Never-Smokers by EGFR Mutation Status: A Brief Report. Journal of thoracic oncology, 20:521-530, 2025

2. Shiraishi K, Takahashi A, Momozawa Y, Daigo Y, Kaneko S, Kawaguchi T, Kunitoh H, Matsumoto S, Horinouchi H, Goto A, Honda T, Shimizu K, Torasawa M, Takayanagi D, Saito M, Saito A, Ohe Y, Watanabe SI, Goto K, Tsuboi M, Tsuchihara K, Takata S, Aoi T, Takano A, Kobayashi M, Miyagi Y, Tanaka K, Suzuki H, Maeda D, Yamaura T, Matsuda M, Shimada Y, Mizuno T, Sakamoto H, Yoshida T, Goto Y, Yoshida T, Yamaji T, Sonobe M, Toyooka S, Yoneda K, Masago K, Tanaka F, Hara M, Fuse N, Nishizuka SS, Motoi N, Sawada N, Nishida Y, Kumada K, Takeuchi K, Tanno K, Yatabe Y, Sunami K, Hishida T, Miyazaki Y, Ito H, Amemiya M, Totsuka H, Nakayama H, Yokose T, Ishigaki K, Nagashima T, Ohtaki Y, Imai K, Takasawa K, Minamiya Y, Kobayashi K, Okubo K, Wakai K, Shimizu A, Yamamoto M, Iwasaki M, Matsuda K, Inazawa J, Shiraishi Y, Nishikawa H, Murakami Y, Kubo M, Matsuda F, Kamatani Y, Hamamoto R, Matsuo K, Kohno T. Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses. Cancer communications (London, England), 44:287-293, 2024

3. Arakawa A, Tao K, Kohno T, Ogawa C. Cross-individual cancer transmission to children during the gestational and perinatal periods. Cancer science, 115:1039-1047, 2024

4. Mochizuki A, Shiraishi K, Honda T, Higashiyama RI, Sunami K, Matsuda M, Shimada Y, Miyazaki Y, Yoshida Y, Watanabe SI, Yatabe Y, Hamamoto R, Kohno T. Passive Smoking-Induced Mutagenesis as a Promoter of Lung Carcinogenesis. Journal of thoracic oncology, 19:984-994, 2024

5. Takasawa K, Asada K, Kaneko S, Shiraishi K, Machino H, Takahashi S, Shinkai N, Kouno N, Kobayashi K, Komatsu M, Mizuno T, Okubo Y, Mukai M, Yoshida T, Yoshida Y, Horinouchi H, Watanabe SI, Ohe Y, Yatabe Y, Kohno T, Hamamoto R. Advances in cancer DNA methylation analysis with methPLIER: use of non-negative matrix factorization and knowledge-based constraints to enhance biological interpretability. Experimental & molecular medicine, 56:646-655, 2024

6. Kato MK, Fujii E, Asami Y, Momozawa Y, Hiranuma K, Komatsu M, Hamamoto R, Ebata T, Matsumoto K, Ishikawa M, Kohno T, Kato T, Yoshida H, Shiraishi K. Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer. Cancer science, 115:1646-1655, 2024

7. Miyakoshi J, Yoshida T, Kashima J, Shirasawa M, Torasawa M, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Shiraishi K, Kohno T, Yamamoto N, Yatabe Y, Suzuki T, Ohe Y. Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression. Lung cancer (Amsterdam, Netherlands), 191:107788, 2024

8. Torasawa M, Yoshida T, Shiraishi K, Goto N, Ueno T, Ichikawa H, Yagishita S, Kohsaka S, Goto Y, Yatabe Y, Hamada A, Mano H, Ohe Y. Rapid Response to Lenvatinib and Disease Flare After Discontinuation in a Patient With Thymic Carcinoma Harboring KIT Exon 11 Mutation: A Case Report. JTO clinical and research reports, 5:100657, 2024

9. Ozawa R, Nishikawa T, Yoshida H, Shiraishi K, Shimoi T, Kato T, Yonemori K. Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers. Journal of gynecologic oncology, 35:e103, 2024

10. Fujii E, Kato MK, Yamaguchi M, Higuchi D, Koyama T, Komatsu M, Hamamoto R, Ishikawa M, Kato T, Kohno T, Shiraishi K, Yoshida H. Genomic profiles of Japanese patients with vulvar squamous cell carcinoma. Scientific reports, 14:13058, 2024

11. Kaneko S, Takasawa K, Asada K, Shiraishi K, Ikawa N, Machino H, Shinkai N, Matsuda M, Masuda M, Adachi S, Takahashi S, Kobayashi K, Kouno N, Bolatkan A, Komatsu M, Yamada M, Miyake M, Watanabe H, Tateishi A, Mizuno T, Okubo Y, Mukai M, Yoshida T, Yoshida Y, Horinouchi H, Watanabe SI, Ohe Y, Yatabe Y, Saloura V, Kohno T, Hamamoto R. Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations. Molecular cancer, 23:126, 2024

12. Nakano S, Yamaji T, Hidaka A, Shimazu T, Shiraishi K, Kuchiba A, Saito M, Kunishima F, Nakaza R, Kohno T, Sawada N, Inoue M, Tsugane S, Iwasaki M. Dietary vitamin D intake and risk of colorectal cancer according to vitamin D receptor expression in tumors and their surrounding stroma. Journal of gastroenterology, 59:825-835, 2024

13. Kato MK, Fujii E, Yamaguchi M, Higuchi D, Asami Y, Hiranuma K, Komatsu M, Hamamoto R, Matumoto K, Kato T, Kohno T, Ishikawa M, Shiraishi K, Yoshida H. Excellent concordance of the molecular classification between preoperative biopsy and final hysterectomy in endometrial carcinoma. Gynecologic oncology, 190:139-145, 2024

14. Fujiwara Y, Takahashi RU, Saito M, Umakoshi M, Shimada Y, Koyama K, Yatabe Y, Watanabe SI, Koyota S, Minamiya Y, Tahara H, Kono K, Shiraishi K, Kohno T, Goto A, Tsuchiya N. Oncofetal IGF2BP3-mediated control of microRNA structural diversity in the malignancy of early-stage lung adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 121:e2407016121, 2024

15. Asada K, Kaneko S, Takasawa K, Shiraishi K, Shinkai N, Shimada Y, Takahashi S, Machino H, Kobayashi K, Bolatkan A, Komatsu M, Yamada M, Miyake M, Watanabe H, Tateishi A, Mizuno T, Okubo Y, Mukai M, Yoshida T, Yoshida Y, Horinouchi H, Watanabe SI, Ohe Y, Yatabe Y, Kohno T, Hamamoto R. Multi-omics and clustering analyses reveal the mechanisms underlying unmet needs for patients with lung adenocarcinoma and identify potential therapeutic targets. Molecular cancer, 23:182, 2024

16. Miwa M, Kitagawa M, Asami Y, Kobayashi-Kato M, Watanabe T, Ogasawara A, Hiranuma K, Kato H, Saito M, Miyagi Y, Kato T, Yoshida H, Momozawa Y, Kohno T, Shiraishi K, Hasegawa K. Prevalence and outcomes of germline pathogenic variants of homologous recombination repair genes in ovarian cancer. Cancer science, 115:3952-3962, 2024

17. Fujii H, Hirano H, Shiraishi K, Shoji H, Hirose T, Okita N, Takashima A, Koyama T, Kato K. Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database. JCO precision oncology, 8:e2400284, 2024

18. Takano Y, Suzuki J, Nomura K, Fujii G, Zenkoh J, Kawai H, Kuze Y, Kashima Y, Nagasawa S, Nakamura Y, Kojima M, Tsuchihara K, Seki M, Kanai A, Matsubara D, Kohno T, Noguchi M, Nakaya A, Tsuboi M, Ishii G, Suzuki Y, Suzuki A. Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development. Nature communications, 15:10637, 2024

19. Takamizawa S, Hirano H, Takashima A, Shoji H, Hirose T, Okita N, Shiraishi K, Sekine S, Takamizawa Y, Kanemitsu Y, Kato K. Clinicopathological and molecular features of claudin-18 isoform 2 expression in patients with colorectal cancer: a single-center retrospective study. Therapeutic advances in medical oncology, 16:17588359241286774, 2024