Annual Report 2020

Division of Cancer Genomics

Tatsuhiro Shibata, Yasushi Totoki, Yasuhito Arai, Natsuko Hama, Hiromi Nakamura, Fumie Hosoda, Hirofumi Rokutan, Mihoko Adachi, Hiroshi Chikuta, Akihiko Fukagawa, Yuuya Kobayashi, Wakako Mukai, Erika Arakawa, Seri Yamagishi, Hiroe Nozaki, Machiko Watanabe

Introduction

 The Division of Cancer Genomics focuses on the 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 (International Cancer Genome Consortium (ICGC) and ICGC-ARGO). We have developed new informatics tools for data analysis from various types of next-generation high-performance sequencers.

Research activities

 We have performed bioinformatics analyses of the whole genome, whole exome, and whole transcriptome of 1,457 gastric cancers, including 697 Japanese cases. The most extensive (1,335 cases) and trans-ethnic landscape of driver events in gastric cancer has been reported, and 84 significantly mutated genes, including 14 previously unreported ones have been identified. We have 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.

 Using a combination of whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and epigenomics sequencing, we have performed an integrated analysis of renal cell carcinomas. The genomic and epigenomic aberration of each histological type has been revealed.

 We have developed an in-house pipeline for detecting somatic structural variants (SVs) from whole-genome sequencing data, and identified 49,059 SVs from 170 gastric cancer genomes. These SVs were classified by unique categories (type, size, distribution, and chromatin status). A total of 38 recurrent hot-spot SVs were found, and novel oncogene candidates were identified. Non-negative Matrix Factorization analysis has 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.

 To develop a novel molecular target therapy, we have explored molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas (BTC) harboring the FGFR2 rearrangements in a prospective multicenter study (PRELUDE). FGFR2 rearrangement was identified in 7.4% cases (20/272) of intrahepatic cholangiocarcinoma (ICC) and 3.6% cases (3/83) of perihilar cholangiocarcinoma (PCC), and was associated with HBV/HCV infection.

 A fraction of sarcomas and brain tumors remain unclassified or are difficult to classify based on the current histologic and immunohistochemical profile. In our genome profiling project for these unclassifiable tumors, driver gene alterations have been identified. BCOR fusions or ITD were identified with NTRK3 overexpression in some adult sarcomas. In unclassified ependymoma-like CNS tumors, C11orf95-NCOA1/2 or –RELA fusions were uncovered.

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 2020

Journal

1. Fujino T, Goyama S, Sugiura Y, Inoue D, Asada S, Yamasaki S, Matsumoto A, Yamaguchi K, Isobe Y, Tsuchiya A, Shikata S, Sato N, Morinaga H, Fukuyama T, Tanaka Y, Fukushima T, Takeda R, Yamamoto K, Honda H, Nishimura EK, Furukawa Y, Shibata T, Abdel-Wahab O, Suematsu M, Kitamura T. Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway. Nat Commun, 12:1826, 2021

2. 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 Pathol, 31:e12943, 2021

3. Arakawa A, Ichikawa H, Kubo T, Motoi N, Kumamoto T, Nakajima M, Yonemori K, Noguchi E, Sunami K, Shiraishi K, Kakishima H, Yoshida H, Hishiki T, Kawakubo N, Kuroda T, Kiyokawa T, Yamada K, Yanaihara N, Takahashi K, Okamoto A, Hirabayashi S, Hasegawa D, Manabe A, Ono K, Matsuoka M, Arai Y, Togashi Y, Shibata T, Nishikawa H, Aoki K, Yamamoto N, Kohno T, Ogawa C. Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. N Engl J Med, 384:42-50, 2021

4. 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 Genet, 17:e1009113, 2021

5. 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 Res, 81:489-500, 2021

6. Tamai S, Nakano Y, Kinoshita M, Sabit H, Nobusawa S, Arai Y, Hama N, Totoki Y, Shibata T, Ichimura K, Nakada M. Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features. Brain Tumor Pathol, 38:64-70, 2021

7. 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). J Gastroenterol, 56:250-260, 2021

8. Murakami F, Tsuboi Y, Takahashi Y, Horimoto Y, Mogushi K, Ito T, Emi M, Matsubara D, Shibata T, Saito M, Murakami Y. Short somatic alterations at the site of copy number variation in breast cancer. Cancer Sci, 112:444-453, 2021

9. Kudo SE, Kouyama Y, Ogawa Y, Ichimasa K, Hamada T, Kato K, Kudo K, Masuda T, Otsu H, Misawa M, Mori Y, Kudo T, Hayashi T, Wakamura K, Miyachi H, Sawada N, Sato T, Shibata T, Hamatani S, Nemoto T, Ishida F, Niida A, Miyano S, Oshima M, Ogino S, Mimori K. Depressed Colorectal Cancer: A New Paradigm in Early Colorectal Cancer. Clin Transl Gastroenterol, 11:e00269, 2020

10. Semba T, Sato R, Kasuga A, Suina K, Shibata T, Kohno T, Suzuki M, Saya H, Arima Y. Lung Adenocarcinoma Mouse Models Based on Orthotopic Transplantation of Syngeneic Tumor-Initiating Cells Expressing EpCAM, SCA-1, and Ly6d. Cancers (Basel), 12:2020

11. Sangatsuda Y, Miura F, Araki H, Mizoguchi M, Hata N, Kuga D, Hatae R, Akagi Y, Amemiya T, Fujioka Y, Arai Y, Yoshida A, Shibata T, Yoshimoto K, Iihara K, Ito T. Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant-specific signature shared with bone tumors. Sci Rep, 10:16162, 2020

12. Bailey MH, Meyerson WU, Dursi LJ, Wang LB, Dong G, Liang WW, Weerasinghe A, Li S, Li Y, Kelso S, Saksena G, Ellrott K, Wendl MC, Wheeler DA, Getz G, Simpson JT, Gerstein MB, Ding L. Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples. Nat Commun, 11:4748, 2020

13. Li CH, Prokopec SD, Sun RX, Yousif F, Schmitz N, Boutros PC. Sex differences in oncogenic mutational processes. Nat Commun, 11:4330, 2020

14. Takai E, Nakamura H, Chiku S, Kubo E, Ohmoto A, Totoki Y, Shibata T, Higuchi R, Yamamoto M, Furuse J, Shimizu K, Takahashi H, Morizane C, Furukawa T, Yachida S. Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer. Ann Surg, 2020

15. Midorikawa Y, Yamamoto S, Tatsuno K, Renard-Guillet C, Tsuji S, Hayashi A, Ueda H, Fukuda S, Fujita T, Katoh H, Ishikawa S, Covington KR, Creighton CJ, Sugitani M, Wheeler DA, Shibata T, Nagae G, Takayama T, Aburatani H. Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression. Cancer Res, 80:3810-3819, 2020

16. Takeda R, Asada S, Park SJ, Yokoyama A, Becker HJ, Kanai A, Visconte V, Hershberger C, Hayashi Y, Yonezawa T, Tamura M, Fukushima T, Tanaka Y, Fukuyama T, Matsumoto A, Yamasaki S, Nakai K, Yamazaki S, Inaba T, Shibata T, Inoue D, Honda H, Goyama S, Maciejewski JP, Kitamura T. HHEX promotes myeloid transformation in cooperation with mutant ASXL1. Blood, 136:1670-1684, 2020

17. Yamada S, Muto J, De Leon JCA, Kumai T, Ito K, Murayama K, Hama N, Nakano Y, Satomi K, Arai Y, Shibata T, Inoue T, Nobusawa S, Ichimura K, Hirose Y, Abe M. Primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation: a similar cytological appearance as its soft tissue counterpart but no lobulation in association with desmoplastic stroma. Brain Tumor Pathol, 37:111-117, 2020

18. Suzuki A, Katoh H, Komura D, Kakiuchi M, Tagashira A, Yamamoto S, Tatsuno K, Ueda H, Nagae G, Fukuda S, Umeda T, Totoki Y, Abe H, Ushiku T, Matsuura T, Sakai E, Ohshima T, Nomura S, Seto Y, Shibata T, Rino Y, Nakajima A, Fukayama M, Ishikawa S, Aburatani H. Defined lifestyle and germline factors predispose Asian populations to gastric cancer. Sci Adv, 6:eaav9778, 2020

19. Niida A, Hasegawa T, Innan H, Shibata T, Mimori K, Miyano S. A unified simulation model for understanding the diversity of cancer evolution. PeerJ, 8:e8842, 2020

20. Umemoto K, Togashi Y, Arai Y, Nakamura H, Takahashi S, Tanegashima T, Kato M, Nishikawa T, Sugiyama D, Kojima M, Gotohda N, Kuwata T, Ikeda M, Shibata T, Nishikawa H. The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. Int Immunol, 32:273-281, 2020