Annual Report 2024
Division of Cancer Genomics
Tatsuhiro Shibata, Yasuhito Arai, Natsuko Hama, Hiromi Nakamura, Mihoko Adachi, Satoshi Shiba, Akihiko Fukagawa, Arisa Hara, Yuko Aoki, Mayumi Kobayashi, Akiko Matsumoto
Introduction
The Division of Cancer Genomics focuses on comprehensive characterization of the cancer genome based on tumor pathology. It aims to make a "breakthrough" by identifying novel cancer-related genes, including potential therapeutic targets and biomarkers, and understanding the cancer genome that contributes to cancer pathogenesis. This division has also participated in the international consortium (ICGC-ARGO, and Mutographs). We have developed new informatics tools for data analysis from various types of next-generation high-performance sequencers.
Research Activities
1. Integrated Metagenomic and Multi-Omics Analysis of Colorectal Cancer in Japanese Patients
In collaboration with various departments at the NCC Hospital, we obtained patient consent for research participation and collected tissue, stool, pancreatic fluid, and other samples. We then proceeded with genomic analysis, metagenomic analysis, and metabolomic analysis using these samples. Using metagenomic data, four subtypes correlated with clinical background and driver mutations were identified from 138 Japanese colorectal cancer cases.
2. International Collaborative Analysis of Colorectal Cancer Mutation Signatures
The incidence of colorectal cancer varies significantly by region and era. Over the past 20 years, young-onset colorectal cancer in individuals under 50 has doubled globally, yet the cause remains unclear. Whole-genome sequencing was performed on 981 colorectal cancer cases from 11 countries, including Japan, to compare mutation signatures. Compared to other regions, Japanese colorectal cancer cases were found to harbour a higher proportion (50% of all cases) of mutation signatures (SBS88 and ID18) derived from colibactin toxin produced by pks+ Escherichia coli. Furthermore, the mutation pattern associated with colibactin toxin was observed at a high frequency in young-onset colorectal cancer (3.3 times higher in those under 40 than in those over 70). It was present in 15% of APC mutations, the earliest driver abnormalities, suggesting that exposure from a young age may correlate with the risk of developing colorectal cancer.
3. Clinical-pathological and Molecular-genetic Analysis of Extrachromosomal DNA (ecDNA) in Gastric Cancer
ecDNA was identified from whole-genome sequencing data of 80 gastric cancer cohort cases. ecDNA was widely detected from early to advanced stages, with limited impact on prognosis. Furthermore, in cases where ecDNA carried immune-regulatory genes, this was associated with suppression of cytotoxic T-cell responses, suggesting ecDNA may be involved in immune evasion. EcDNA-positive cases were characterised by TP53 mutations and microsatellite stability (MSS). Additionally, mutational signature analysis indicated gastric acid-induced oxidative stress may contribute to ecDNA generation in gastric cancer.
4. New Anticancer Agent Developed from Biliary Tract Cancer Genome Analysis Receives Approval
For biliary tract cancer, a refractory cancer with high unmet medical need, the FGFR2 fusion gene was identified as a therapeutic target. Eisai Co., Ltd. developed the FGFR kinase inhibitor tasulagatinib (E7090), and its antitumour efficacy was confirmed in non-clinical studies. Through a multi-centre collaborative study with the Hospital and the Hospital East, development of a FISH diagnostic kit and screening studies using fixed specimens were advanced. Efficacy was demonstrated in an international Phase II trial (Study 201) (ORR=30.2%). Consequently, tasulagatinib was approved as a new drug in September 2024 for the indication of efficacy and effect in ‘FGFR2 fusion gene-positive, unresectable biliary tract cancer that has worsened after cancer chemotherapy’.
Future Prospects
By utilizing current and cutting-edged sequencing technologies (e.g., long-read and single-cell sequencing), this division will actively investigate the cancer genomics from both basic (new biomarkers including therapeutic targets, epigenomics, metagenomics, and immune-genomics) and translational research (preclinical research, liquid clinical sequencing, and germline evaluation) viewpoints. Pervasive collaboration with cancer-immunology groups by applying single-cell immune-profiling and TCR repertoire sequencing will be achieved. This division will also contribute to developing bioinformatics tools and human resources to analyze extensive cancer genomics data.
List of papers published in 2024
Journal
1. Mizutani S, Tamaki A, Shiba S, Salim F, Yamada M, Takamaru H, Nakajima T, Yoshida N, Ikuta S, Yachida T, Shibata T, Soga T, Saito Y, Fukuda S, Ishikawa H, Yamada T, Yachida S. Dynamics of the gut microbiome in FAP patients undergoing intensive endoscopic reduction of polyp burden. Gut, 74:335-338, 2025
2. Nakata S, Arai Y, Fukuoka K, Shirakura T, Yamazaki A, Osawa S, Hama N, Shibata T, Miyagishima T, Horiguchi K, Tosaka M, Yokoo H, Yoshimoto Y, Nobusawa S. Pediatric diffuse glioma with EP300::BCOR fusion manifesting as low-grade epilepsy-associated neuroepithelial tumor: a case presentation. Brain tumor pathology, 41:35-39, 2024
3. Perdomo S, Abedi-Ardekani B, de Carvalho AC, Ferreiro-Iglesias A, Gaborieau V, Cattiaux T, Renard H, Chopard P, Carreira C, Spanu A, Nikmanesh A, Cardoso Penha RC, Antwi SO, Ashton-Prolla P, Canova C, Chitapanarux T, Cox R, Curado MP, de Oliveira JC, Dzamalala C, Fabianova E, Ferri L, Fitzgerald R, Foretova L, Gallinger S, Goldstein AM, Holcatova I, Huertas A, Janout V, Jarmalaite S, Kaneva R, Kowalski LP, Kulis T, Lagiou P, Lissowska J, Malekzadeh R, Mates D, McCorrmack V, Menya D, Mhatre S, Mmbaga BT, de Moricz A, Nyirády P, Ognjanovic M, Papadopoulou K, Polesel J, Purdue MP, Rascu S, Rebolho Batista LM, Reis RM, Ribeiro Pinto LF, Rodríguez-Urrego PA, Sangkhathat S, Sangrajrang S, Shibata T, Stakhovsky E, Świątkowska B, Vaccaro C, Vasconcelos de Podesta JR, Vasudev NS, Vilensky M, Yeung J, Zaridze D, Zendehdel K, Scelo G, Chanudet E, Wang J, Fitzgerald S, Latimer C, Moody S, Humphreys L, Alexandrov LB, Stratton MR, Brennan P. The Mutographs biorepository: A unique genomic resource to study cancer around the world. Cell genomics, 4:100500, 2024
4. Fukuda H, Arai K, Mizuno H, Nishito Y, Motoi N, Arai Y, Hiraoka N, Shibata T, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Maruyama T, Kuwabara K, Nishizawa T, Mizoguchi Y, Yoshida Y, Watanabe SI, Yamashita M, Kitano S, Sakamoto H, Nagata Y, Mitsumori R, Ozaki K, Niida S, Kanai Y, Hirayama A, Soga T, Tsukada K, Yabuki N, Shimada M, Kitazawa T, Natori O, Sawada N, Kato A, Yoshida T, Yasuda K, Ochiai A, Tsunoda H, Aoki K. Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments. Cancer science, 115:1763-1777, 2024
5. Rokutan H, Arai Y, Kunita A, Yamasaki S, Nakamura H, Hama N, Nakayama A, Hosoda F, Totoki Y, Fujishiro M, Seto Y, Shibata T, Ushiku T. Genomic and Pathologic Profiling of Very Well-Differentiated Gastric Adenocarcinoma of Intestinal Type: A Study With Emphasis on Diffuse-Type Transformation. The American journal of surgical pathology, 48:652-661, 2024
6. Hashimoto M, Kojima Y, Sakamoto T, Ozato Y, Nakano Y, Abe T, Hosoda K, Saito H, Higuchi S, Hisamatsu Y, Toshima T, Yonemura Y, Masuda T, Hata T, Nagayama S, Kagawa K, Goto Y, Utou M, Gamachi A, Imamura K, Kuze Y, Zenkoh J, Suzuki A, Takahashi K, Niida A, Hirose H, Hayashi S, Koseki J, Fukuchi S, Murakami K, Yoshizumi T, Kadomatsu K, Tobo T, Oda Y, Uemura M, Eguchi H, Doki Y, Mori M, Oshima M, Shibata T, Suzuki Y, Shimamura T, Mimori K. Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis. EBioMedicine, 103:105102, 2024
7. Senkin S, Moody S, Díaz-Gay M, Abedi-Ardekani B, Cattiaux T, Ferreiro-Iglesias A, Wang J, Fitzgerald S, Kazachkova M, Vangara R, Le AP, Bergstrom EN, Khandekar A, Otlu B, Cheema S, Latimer C, Thomas E, Atkins JR, Smith-Byrne K, Cortez Cardoso Penha R, Carreira C, Chopard P, Gaborieau V, Keski-Rahkonen P, Jones D, Teague JW, Ferlicot S, Asgari M, Sangkhathat S, Attawettayanon W, Świątkowska B, Jarmalaite S, Sabaliauskaite R, Shibata T, Fukagawa A, Mates D, Jinga V, Rascu S, Mijuskovic M, Savic S, Milosavljevic S, Bartlett JMS, Albert M, Phouthavongsy L, Ashton-Prolla P, Botton MR, Silva Neto B, Bezerra SM, Curado MP, Zequi SC, Reis RM, Faria EF, de Menezes NS, Ferrari RS, Banks RE, Vasudev NS, Zaridze D, Mukeriya A, Shangina O, Matveev V, Foretova L, Navratilova M, Holcatova I, Hornakova A, Janout V, Purdue MP, Rothman N, Chanock SJ, Ueland PM, Johansson M, McKay J, Scelo G, Chanudet E, Humphreys L, de Carvalho AC, Perdomo S, Alexandrov LB, Stratton MR, Brennan P. Geographic variation of mutagenic exposures in kidney cancer genomes. Nature, 629:910-918, 2024