Annual Report 2023

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. Whole genome and epigenomic analysis in Japanese renal cell carcinoma

 Whole genome and transcriptome analyses of Japanese renal cell carcinoma cases were complemented by epigenomic sequencing and analyzed in an integrated manner. Master transcription factors in each histological type were identified from motif sequences enriched in open chromatin regions.

2. Integrated metagenomic and multi-omic analysis of Japanese colorectal cancer

 In collaboration with the departments of the NCC Hospital, tissue, stool and pancreatic fluid samples were collected, and genomic, metagenomic and metabolomic analyses were performed on these samples. In addition, lifestyle questionnaire data (JPHC-NEXT FFQ) were collected for metagenomic and multi-omics integrated analysis. Metagenomic data identified four subtypes correlated with clinical background and driver abnormalities in 138 Japanese colorectal cancer cases. Metabolomic data identified colorectal cancer subtypes correlated with prognosis and further identified several metabolites that differed between good and poor prognosis groups.

3. Genomic analysis of rare cancers

 We performed genomic analysis of rare cancers, particularly unclassifiable cases of sarcoma and brain tumors. An EP300-BCOR fusion gene was identified in a case of pediatric diffuse glioma with features of a low-grade epileptogenic tumor (LEAT).

4. Development of information analysis tools

 Tools have been developed to assess the impact of genomic mutations occurring in regulatory regions on oncogenesis.

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 2023

Journal

1. 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

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. Shida D, Kuchiba A, Shibata T, Hamaguchi T, Yamasaki S, Ito M, Kobatake T, Tonooka T, Masaki T, Shiozawa M, Takii Y, Uetake H, Okamura S, Ojima H, Kazama S, Takeyama H, Kanato K, Shimada Y, Murakami Y, Kanemitsu Y. Genomic landscape and its prognostic significance in stage III colorectal cancer: JCOG1506A1, an ancillary of JCOG0910. Cancer science, 114:3352-3363, 2023

5. Aoki K, Nishito Y, Motoi N, Arai Y, Hiraoka N, Shibata T, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Nishizawa T, Fukuda H, Ohashi K, Arai K, 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, Maruyama T, Tsukada K, Yabuki N, Shimada M, Kitazawa T, Natori O, Sawada N, Kato A, Yoshida T, Yasuda K, Mizuno H, Tsunoda H, Ochiai A. Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations. Cancer research communications, 3:1026-1040, 2023

6. Fukagawa A, Hama N, Totoki Y, Nakamura H, Arai Y, Saito-Adachi M, Maeshima A, Matsui Y, Yachida S, Ushiku T, Shibata T. Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort. Nature communications, 14:8383, 2023

7. Terada M, Nakamura K, Matsuda T, Okuma HS, Sudo K, Yusof A, Imasa M, Sirachainan E, Anh PT, Fujiwara Y, Yamamoto N, Voon PJ, Chokephaibulkit K, Shibata T, Inoue M, Mano H, Shimoi T, Sriuranpong V, Yonemori K, Shimada K. A new era of the Asian clinical research network: a report from the ATLAS international symposium. Japanese journal of clinical oncology, 53:619-628, 2023

8. Kobayashi Y, Niida A, Nagayama S, Saeki K, Haeno H, Takahashi KK, Hayashi S, Ozato Y, Saito H, Hasegawa T, Nakamura H, Tobo T, Kitagawa A, Sato K, Shimizu D, Hirata H, Hisamatsu Y, Toshima T, Yonemura Y, Masuda T, Mizuno S, Kawazu M, Kohsaka S, Ueno T, Mano H, Ishihara S, Uemura M, Mori M, Doki Y, Eguchi H, Oshima M, Suzuki Y, Shibata T, Mimori K. Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers. British journal of cancer, 129:1105-1118, 2023

9. Totoki Y, Saito-Adachi M, Shiraishi Y, Komura D, Nakamura H, Suzuki A, Tatsuno K, Rokutan H, Hama N, Yamamoto S, Ono H, Arai Y, Hosoda F, Katoh H, Chiba K, Iida N, Nagae G, Ueda H, Shihang C, Sekine S, Abe H, Nomura S, Matsuura T, Sakai E, Ohshima T, Rino Y, Yeoh KG, So J, Sanghvi K, Soong R, Fukagawa A, Yachida S, Kato M, Seto Y, Ushiku T, Nakajima A, Katai H, Tan P, Ishikawa S, Aburatani H, Shibata T. Multiancestry genomic and transcriptomic analysis of gastric cancer. Nature genetics, 55:581-594, 2023

10. Abe H, Rokutan H, Totoki Y, Nakamura H, Shibata T, Ushiku T, Fukayama M. Lost expression of AT-rich interaction domain 1A in the gastric mucosa-A constituent of field cancerization in the stomach. Pathology international, 73:234-245, 2023

11. Kitagawa A, Osawa T, Noda M, Kobayashi Y, Aki S, Nakano Y, Saito T, Shimizu D, Komatsu H, Sugaya M, Takahashi J, Kosai K, Takao S, Motomura Y, Sato K, Hu Q, Fujii A, Wakiyama H, Tobo T, Uchida H, Sugimachi K, Shibata K, Utsunomiya T, Kobayashi S, Ishii H, Hasegawa T, Masuda T, Matsui Y, Niida A, Soga T, Suzuki Y, Miyano S, Aburatani H, Doki Y, Eguchi H, Mori M, Nakayama KI, Shimamura T, Shibata T, Mimori K. Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma. British journal of cancer, 128:2206-2217, 2023

12. Rizq O, Mimura N, Oshima M, Momose S, Takayama N, Itokawa N, Koide S, Shibamiya A, Miyamoto-Nagai Y, Rizk M, Nakajima-Takagi Y, Aoyama K, Wang C, Saraya A, Ito R, Seimiya M, Watanabe M, Yamasaki S, Shibata T, Yamaguchi K, Furukawa Y, Chiba T, Sakaida E, Nakaseko C, Tamaru JI, Tai YT, Anderson KC, Honda H, Iwama A. UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease. Leukemia, 37:1895-1907, 2023

13. Shiraishi Y, Koya J, Chiba K, Okada A, Arai Y, Saito Y, Shibata T, Kataoka K. Precise characterization of somatic complex structural variations from tumor/control paired long-read sequencing data with nanomonsv. Nucleic acids research, 51:e74, 2023

14. Saito-Adachi M, Hama N, Totoki Y, Nakamura H, Arai Y, Hosoda F, Rokutan H, Yachida S, Kato M, Fukagawa A, Shibata T. Oncogenic structural aberration landscape in gastric cancer genomes. Nature communications, 14:3688, 2023

15. Nocini R, Tondulli L, D'Ambrosio C, Luchini C, Biankin AV, Casolino R, Scarpa A, Milella M, Lawlor RT. ICGC ARGO precision medicine: genomic profiling-informed prediction of immunotherapy response in two patients with metastatic head and neck squamous cell carcinoma. The Lancet. Oncology, 24:851-853, 2023

16. Shimomura K, Hattori N, Iida N, Muranaka Y, Sato K, Shiraishi Y, Arai Y, Hama N, Shibata T, Narushima D, Kato M, Takamaru H, Okamoto K, Takeda H. Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development. Nature communications, 14:6514, 2023