Annual Report 2022

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

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.  Comprehensive genomic analysis of refractory solid tumors important in Japan and other Asian countries and international collaboration

 We performed the world's largest multi-ethnic analysis of gastric cancer mutation signatures with over 1,400 cases and found that the alcohol consumption-associated mutation signature SBS16 is strongly associated with a hot spot mutation (Y42C) in RHOA, a driver gene for refractory diffuse gastric cancer. We also found that individuals with a weak acetaldehyde degradation genotype (ALDH2 rs671 AA/AG) had higher levels of SBS16 mutations.

2.  Analysis of chromosomal structural aberrations by whole-genome analysis

 Based on the whole-genome data of 170 gastric cancer cases, we identified the locations of chromosomal structural aberrations and classified the profiles according to the characteristics of the chromosomal aberrations. Recurrent oncogene amplification by extrachromosomal DNA was observed. Whole genome analysis of gastrointestinal cancers by nanopore sequencing was performed to classify structural mutations.

3.  Integrated analysis of gut microbiota in Japanese cases

 We analyzed the gut microbiota and metabolites in Japanese patients with gastrointestinal tumors (including hereditary tumors). We performed correlation analysis between metagenomic and genomic analysis for Japanese colorectal cancer and found a characteristic group of patients with poor prognosis and immune inactivation.

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 2022

Journal

1. 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

2. Liu X, Sato N, Yabushita T, Li J, Jia Y, Tamura M, Asada S, Fujino T, Fukushima T, Yonezawa T, Tanaka Y, Fukuyama T, Tsuchiya A, Shikata S, Iwamura H, Kinouchi C, Komatsu K, Yamasaki S, Shibata T, Sasaki AT, Schibler J, Wunderlich M, O’Brien E, Mizukawa B, Mulloy JC, Sugiura Y, Takizawa H, Shibata T, Miyake K, Kitamura T, Goyama S. IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia. EMBO molecular medicine, 15:e15631, 2023

3. Ozato Y, Kojima Y, Kobayashi Y, Hisamatsu Y, Toshima T, Yonemura Y, Masuda T, Kagawa K, Goto Y, Utou M, Fukunaga M, Gamachi A, Imamura K, Kuze Y, Zenkoh J, Suzuki A, Niida A, Hirose H, Hayashi S, Koseki J, Oki E, Fukuchi S, Murakami K, Tobo T, Nagayama S, Uemura M, Sakamoto T, Oshima M, Doki Y, Eguchi H, Mori M, Iwasaki T, Oda Y, Shibata T, Suzuki Y, Shimamura T, Mimori K. Spatial and single-cell transcriptomics decipher the cellular environment containing HLA-G+ cancer cells and SPP1+ macrophages in colorectal cancer. Cell reports, 42:111929, 2023

4. Nagayama S, Kobayashi Y, Fukunaga M, Sakimura S, Sugimachi K, Sasaki S, Masuda T, Mafune KI, Oshima M, Shibata T, Suzuki Y, Mimori K. Mutated genes on ctDNA detecting postoperative recurrence presented reduced neoantigens in primary tumors in colorectal cancer cases. Scientific reports, 13:1366, 2023

5. 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, 24:1246-1258, 2022

6. Nagane M, Ichimura K, Onuki R, Narushima D, Honda-Kitahara M, Satomi K, Tomiyama A, Arai Y, Shibata T, Narita Y, Uzuka T, Nakamura H, Nakada M, Arakawa Y, Ohnishi T, Mukasa A, Tanaka S, Wakabayashi T, Aoki T, Aoki S, Shibui S, Matsutani M, Ishizawa K, Yokoo H, Suzuki H, Morita S, Kato M, Nishikawa R. Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study. Cancers, 14:5522, 2022

7. Satoh H, Arai Y, Furukawa E, Moriguchi T, Hama N, Urushidate T, Totoki Y, Kato M, Ohe Y, Yamamoto M, Shibata T. Genomic landscape of chemical-induced lung tumors under Nrf2 different expression levels. Carcinogenesis, 43:613-623, 2022

8. Katsuya Y, Kitano S, Yamashita M, Ouchi M, Yagishita S, Hamada A, Nakamura H, Hosoda F, Shibata T, Motoi N, Nakayama T, Seto T, Umemura S, Hosomi Y, Satouchi M, Nishio M, Kozuki T, Hida T, Ohe Y, Horinouchi H. Comprehensive biomarker analysis from phase II study of nivolumab in patients with thymic carcinoma. Frontiers in oncology, 12:966527, 2022

9. Kojima N, Arai Y, Satomi K, Kubo T, Matsushita Y, Mori T, Matsushita H, Ushijima T, Yatabe Y, Shibata T, Yonemori K, Ichimura K, Ichikawa H, Kawai A, Yoshida A. Co-expression of ERG and CD31 in a subset of CIC-rearranged sarcoma: a potential diagnostic pitfall. Modern pathology, 35:1439-1448, 2022

10. Yamazaki A, Arai Y, Fukuoka K, Nakano Y, Hama N, Nakata S, Makino K, Kuroda JI, Shinojima N, Mukasa A, Mikami Y, Ichimura K, Shibata T, Yokoo H, Nobusawa S. Diffusely infiltrating glioma with CREBBP-BCORL1 fusion showing overexpression of not only BCORL1 but BCOR: A case report. Brain tumor pathology, 39:171-178, 2022

11. Mafficini A, Simbolo M, Shibata T, Hong SM, Pea A, Brosens LA, Cheng L, Antonello D, Sciammarella C, Cantù C, Mattiolo P, Taormina SV, Malleo G, Marchegiani G, Sereni E, Corbo V, Paolino G, Ciaparrone C, Hiraoka N, Pallaoro D, Jansen C, Milella M, Salvia R, Lawlor RT, Adsay V, Scarpa A, Luchini C. Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma. Modern pathology, 35:1929-1943, 2022

12. Kotani D, Nakamura Y, Fujisawa T, Bando H, Sakamoto N, Johns AL, Park K, Casolino R, Yoshino T, Biankin AV. ICGC-ARGO precision medicine: targeted therapy according to longitudinal assessment of tumour heterogeneity in colorectal cancer. The Lancet. Oncology, 23:463-464, 2022

13. 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

14. 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

15. 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

16. Tanaka M, Kunita A, Yamagishi M, Katoh H, Ishikawa S, Yamamoto H, Abe J, Arita J, Hasegawa K, Shibata T, Ushiku T. KRAS mutation in intrahepatic cholangiocarcinoma: Linkage with metastasis-free survival and reduced E-cadherin expression. Liver international, 42:2329-2340, 2022

17. Oba U, Kohashi K, Sangatsuda Y, Oda Y, Sonoda KH, Ohga S, Yoshimoto K, Arai Y, Yachida S, Shibata T, Ito T, Miura F. An efficient procedure for the recovery of DNA from formalin-fixed paraffin-embedded tissue sections. Biology methods & protocols, 7:bpac014, 2022

18. Kagamu H, Yamasaki S, Kitano S, Yamaguchi O, Mouri A, Shiono A, Nishihara F, Miura Y, Hashimoto K, Imai H, Kaira K, Kobayashi K, Kanai Y, Shibata T, Horimoto K. Single-Cell Analysis Reveals a CD4+ T-cell Cluster That Correlates with PD-1 Blockade Efficacy. Cancer research, 82:4641-4653, 2022