Annual Report 2021

Division of Cancer Genomics

Tatsuhiro Shibata, Yasushi Totoki, Yasuhito Arai, Hiromi Watanabe, Natsuko Hama, Mihoko Adachi, Satoshi Shiba, Akihiko Fukagawa, Erika Arakawa, Arisa Hara, Akiko Matsumoto, Fumie Hosoda, Machiko Watanabe

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's pathogenesis. This Division has also participated in international consortiums (ICGC-ARGO, and Mutographs). We have developed new informatics tools for data analysis from various types of next-generation high-performance sequencers.

Research activities

 We performed bioinformatics analyses of the whole genome, whole exome, and whole transcriptome of 1,457 gastric cancers, including 697 Japanese cases. We reported the most extensive (1,335 cases) and trans-ethnic landscape of driver events in gastric cancer and identified 77 significantly mutated genes. We also identified characteristic mutational signatures correlated with ethnic groups, subtypes, epidemiological risk factors, and clinical information. We discovered a novel connection between a driver gene and a mutational signature and identified a potentially preventable portion. An integrated analysis of whole genome sequencing and metagenomic sequencing of Japanese colorectal cancers has been conducted.

 We have developed an in-house pipeline for detecting somatic structural variants (SVs) from whole-genome sequencing data and identified 29 recurrent hot-spot SVs including novel oncogene candidates. Non-negative Matrix Factorization analysis extracted six SV signatures. Based on these SV signatures, gastric cancer samples were divided into seven SV subtypes associated with unique driver events and epidemiological backgrounds.

 We have performed an integrated analysis of renal cell carcinomas using a combination of whole-genome sequencing, RNA sequencing, and epigenomics sequencing. We revealed each histological type’s genomic and epigenomic aberrations, correlating with unique immune microenvironments.

 To develop a novel molecular target therapy, we have explored molecular detection and clinicopathological characteristics of 432 advanced/recurrent biliary tract carcinomas (BTC) harboring the FGFR2 rearrangements in a prospective multicenter study (PRELUDE). Based on the current histologic and immunohistochemical profile, a fraction of sarcomas and brain tumors remain unclassified or challenging to classify. In our genome profiling project for these unclassifiable tumors, we identified novel SSX1 fusions, molecular features discriminating CIC-rearranged sarcoma and angiosarcoma, and CREBBP-BCORL1 fusions.

Future Prospects

 By utilizing current and cutting-edge 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 2021

Journal

1. Yachida S, Totoki Y, Noë M, Nakatani Y, Horie M, Kawasaki K, Nakamura H, Saito-Adachi M, Suzuki M, Takai E, Hama N, Higuchi R, Hirono S, Shiba S, Kato M, Furukawa E, Arai Y, Rokutan H, Hashimoto T, Mitsunaga S, Kanda M, Tanaka H, Takata S, Shimomura A, Oshima M, Hackeng WM, Okumura T, Okano K, Yamamoto M, Yamaue H, Morizane C, Arihiro K, Furukawa T, Sato T, Kiyono T, Brosens LAA, Wood LD, Hruban RH, Shibata T . Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System. Cancer discovery, 12:692-711, 2022

2. Yoshida A, Arai Y, Satomi K, Kubo T, Ryo E, Matsushita Y, Hama N, Sudo K, Komiyama M, Yatabe Y, Shibata T, Ichikawa H, Ichimura K, Kawai A, Mori T. Identification of novel SSX1 fusions in synovial sarcoma. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc, 35:228-239, 2022

3. Milella M, Luchini C, Lawlor RT, Johns AL, Casolino R, Yoshino T, Biankin AV. ICGC-ARGO precision medicine: familial matters in pancreatic cancer. The Lancet. Oncology, 23:25-26, 2022

4. Takami H, Elzawahry A, Mamatjan Y, Fukushima S, Fukuoka K, Suzuki T, Yanagisawa T, Matsushita Y, Nakamura T, Satomi K, Tanaka S, Mukasa A, Saito N, Kanamori M, Kumabe T, Tominaga T, Kobayashi K, Nagane M, Iuchi T, Tamura K, Maehara T, Sugiyama K, Yoshimoto K, Sakai K, Nonaka M, Asai A, Yokogami K, Takeshima H, Narita Y, Shibui S, Nakazato Y, Hama N, Totoki Y, Kato M, Shibata T, Nishikawa R, Matsutani M, Ichimura K. Transcriptome and Methylome Analysis of CNS Germ Cell Tumor Finds its Cell-of-Origin in Embryogenesis and Reveals Shared Similarities with Testicular Counterparts. Neuro-oncology, 2022

5. Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga JI, Imaizumi Y, Watanabe M, Saito Y, Ito Y, McClure MB, Tabata M, Shingaki S, Yoshifuji K, Chiba K, Okada A, Kakiuchi N, Nannya Y, Kamiunten A, Tahira Y, Akizuki K, Sekine M, Shide K, Hidaka T, Kubuki Y, Kitanaka A, Hidaka M, Nakano N, Utsunomiya A, Sica RA, Acuna-Villaorduna A, Janakiram M, Shah U, Ramos JC, Shibata T, Takeuchi K, Takaori-Kondo A, Miyazaki Y, Matsuoka M, Ishitsuka K, Shiraishi Y, Miyano S, Ogawa S, Ye BH, Shimoda K, Kataoka K. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood, 139:967-982, 2022

6. Shiroma H, Shiba S, Erawijantari PP, Takamaru H, Yamada M, Sakamoto T, Kanemitsu Y, Mizutani S, Soga T, Saito Y, Shibata T, Fukuda S, Yachida S, Yamada T. Surgical Treatment for Colorectal Cancer Partially Restores Gut Microbiome and Metabolome Traits. mSystems, 7:e0001822, 2022

7. Takai E, Omata W, Totoki Y, Nakamura H, Shiba S, Takahashi A, Namikawa K, Mori T, Yamazaki N, Shibata T, Yachida S. Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma. Cancer science, 112:4748-4757, 2021

8. Hirata H, Niida A, Kakiuchi N, Uchi R, Sugimachi K, Masuda T, Saito T, Kageyama SI, Motomura Y, Ito S, Yoshitake T, Tsurumaru D, Nishimuta Y, Yokoyama A, Hasegawa T, Chiba K, Shiraishi Y, Du J, Miura F, Morita M, Toh Y, Hirakawa M, Shioyama Y, Ito T, Akimoto T, Miyano S, Shibata T, Mori M, Suzuki Y, Ogawa S, Ishigami K, Mimori K. The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under Chemoradiotherapy. Cancer research, 81:4926-4938, 2021

9. Ono H, Arai Y, Furukawa E, Narushima D, Matsuura T, Nakamura H, Shiokawa D, Nagai M, Imai T, Mimori K, Okamoto K, Hippo Y, Shibata T, Kato M. Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model. BMC biology, 19:207, 2021

10. Moody S, Senkin S, Islam SMA, Wang J, Nasrollahzadeh D, Cortez Cardoso Penha R, Fitzgerald S, Bergstrom EN, Atkins J, He Y, Khandekar A, Smith-Byrne K, Carreira C, Gaborieau V, Latimer C, Thomas E, Abnizova I, Bucciarelli PE, Jones D, Teague JW, Abedi-Ardekani B, Serra S, Scoazec JY, Saffar H, Azmoudeh-Ardalan F, Sotoudeh M, Nikmanesh A, Poustchi H, Niavarani A, Gharavi S, Eden M, Richman P, Campos LS, Fitzgerald RC, Ribeiro LF, Soares-Lima SC, Dzamalala C, Mmbaga BT, Shibata T, Menya D, Goldstein AM, Hu N, Malekzadeh R, Fazel A, McCormack V, McKay J, Perdomo S, Scelo G, Chanudet E, Humphreys L, Alexandrov LB, Brennan P, Stratton MR. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence. Nature genetics, 53:1553-1563, 2021

11. Shibata T. Genomic landscape of hepatocarcinogenesis. Journal of human genetics, 66:845-851, 2021

12. Suzuki M, Saito-Adachi M, Arai Y, Fujiwara Y, Takai E, Shibata S, Seki M, Rokutan H, Maeda D, Horie M, Suzuki Y, Shibata T, Kiyono T, Yachida S. E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer. Cancer research, 81:489-500, 2021

13. Tomomasa R, Arai Y, Kawabata-Iwakawa R, Fukuoka K, Nakano Y, Hama N, Nakata S, Suzuki N, Ishi Y, Tanaka S, Takahashi JA, Yuba Y, Shiota M, Natsume A, Kurimoto M, Shiba Y, Aoki M, Nabeshima K, Enomoto T, Inoue T, Fujimura J, Kondo A, Yao T, Okura N, Hirose T, Sasaki A, Nishiyama M, Ichimura K, Shibata T, Hirato J, Yokoo H, Nobusawa S. Ependymoma-like tumor with mesenchymal differentiation harboring C11orf95-NCOA1/2 or -RELA fusion: A hitherto unclassified tumor related to ependymoma. Brain pathology (Zurich, Switzerland), 31:e12943, 2021

14. Sakimura S, Nagayama S, Fukunaga M, Hu Q, Kitagawa A, Kobayashi Y, Hasegawa T, Noda M, Kouyama Y, Shimizu D, Saito T, Niida A, Tsuruda Y, Otsu H, Matsumoto Y, Uchida H, Masuda T, Sugimachi K, Sasaki S, Yamada K, Takahashi K, Innan H, Suzuki Y, Nakamura H, Totoki Y, Mizuno S, Ohshima M, Shibata T, Mimori K. Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases. PLoS genetics, 17:e1009113, 2021

15. Niida A, Mimori K, Shibata T, Miyano S. Modeling colorectal cancer evolution. Journal of human genetics, 66:869-878, 2021

16. Maruki Y, Morizane C, Arai Y, Ikeda M, Ueno M, Ioka T, Naganuma A, Furukawa M, Mizuno N, Uwagawa T, Takahara N, Kanai M, Asagi A, Shimizu S, Miyamoto A, Yukisawa S, Kadokura M, Kojima Y, Furuse J, Nakajima TE, Sudo K, Kobayashi N, Hama N, Yamanaka T, Shibata T, Okusaka T. Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study). Journal of gastroenterology, 56:250-260, 2021