Annual Report 2017

Tatsuhiro Shibata, Fumie Hosoda, Yasushi Totoki, Shinichi Yachida, Yasuhito Arai, Natsuko Hama, Hiromi Nakamura, Hirofumi Rokutan, Erina Takai, Ogura Koichi, Akihiro Oomoto, Mihoko Adachi, Masami Suzuki, Wakako Mukai, Erika Arakawa, Hiroshi Chikuta, Seri Yamagishi, Hiroe Nozaki, Machiko Watanabe, Risa Usui, Hiroki Sato, Machiko Watanabe, Arisa Kaya, Kazuko Murakami

Introduction

 The Division of Cancer Genomics focuses on comprehensive characterization of the cancer genome on the basis of tumor pathology and aims to make a "breakthrough" by identifying novel cancer-related genes, including potential therapeutic targets and biomarkers, and to under-

stand the cancer genome as heterogeneous but

intervention-able "biological systems" that contribute to the pathogenesis of cancer. This division has also been participating in the international consortium (International Cancer Genome Consortium: ICGC), contributed to the core facility of the National Cancer Center (NCC), and been developing new informatics tools for data analysis from various types of next-generation high-performance sequencers (NGS).

Research activities

1. Comprehensive genomic analysis of intractable solid cancers in Asia

 Collaborating with TCGA (The Cancer Genome Atlas), comprehensive molecular analysis of hepatocellular carcinoma (HCC) has been conducted. Accumulating the largest (1,340 cases) HCC genome data revealed the most comprehensive and precise driver gene landscape. With researchers in the National Cancer Institute (NCI) in the U.S. and Thailand, international correlation of molecular subtypes in liver cancer has been performed.

 ICGC cholangiocarcinoma (CCA) project analyzed the largest cohort (489 cases) and identified prognosis-associated subtypes with unique therapeutic targets. In PRELUDE (genomic screening consortium for biliary tract cancer) for the prospective study of genotype-based molecular therapy, establishing molecular diagnosis of FGFR2 fusion genes in CCA promoted umbrella-

type clinical trials of FGFR2 inhibitors.

 Deterministic driver genes in early gastric neoplasms have been identified.

2. Rare cancer genomics

 Integrated genetic and epigenetic analysis of myxofibrosarcoma identified driver gene landscape including a novel BRAF fusion gene, and molecular subtype associated with prognosis and characteristic immune signature. RNA sequencing of sarcoma with unknown driver genes have been conducted. HTLV1 genome sequencing was performed in virus carrier samples.

3. Immune and microbiome profiling

 We investigated clonal evolution, based on sequencing data of multiple time series using plasma cell-free tumor DNA in patients with melanoma who suffered the immune checkpoint inhibitor therapy. T cell repertoire and immune profiling were conducted in a wide range of solid cancers.

 We are also collecting frozen stool samples in >2,600 subjects (e.g. patients with colorectal carcinoma, healthy individuals) undergoing total colonoscopy in the National Cancer Center Hospital (NCCH). Metagenome and metabolomics analysis uncovered microbial imbalances dramatically change during tumor progression.

4. Development of data analysis pipeline

 A new analytical tool to efficiently detect chromosomal rearrangements from whole genome sequencing data has been developed and applied to CCA and gastric cancer data to detect novel driver events.

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, PGx and germline evaluation) viewpoints. Especially tighter collaboration with cancer-immunology groups by applying single cell immune-profiling and TCR repertoire sequencing will be achieved. This division will also contribute to the development of bioinformatics tools and human resources for analyzing the large cancer genomics data.

List of papers published in January 2017 - March 2018

Journal

 1. Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 169:1327-1341.e23, 2017

 2. Kawazu M, Kojima S, Ueno T, Totoki Y, Nakamura H, Kunita A, Qu W, Yoshimura J, Soda M, Yasuda T, Hama N, Saito-Adachi M, Sato K, Kohsaka S, Sai E, Ikemura M, Yamamoto S, Ogawa T, Fukayama M, Tada K, Seto Y, Morishita S, Hazama S, Shibata T, Yamashita Y, Mano H. Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. PLoS Genet, 13:e1006853, 2017

 3. Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon SM, Forgues M, Pomyen Y, Bhudhisawasdi V, Lertprasertsuke N, Chotirosniramit A, Pairojkul C, Auewarakul CU, Sricharunrat T, Phornphutkul K, Sangrajrang S, Cam M, He P, Hewitt SM, Ylaya K, Wu X, Andersen JB, Thorgeirsson SS, Waterfall JJ, Zhu YJ, Walling J, Stevenson HS, Edelman D, Meltzer PS, Loffredo CA, Hama N, Shibata T, Wiltrout RH, Harris CC, Mahidol C, Ruchirawat M, Wang XW. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell, 32:57-70.e3, 2017

 4. Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, Nellore V, Kongpetch S, Ng AWT, Ng LM, Choo SP, Myint SS, Thanan R, Nagarajan S, Lim WK, Ng CCY, Boot A, Liu M, Ong CK, Rajasegaran V, Lie S, Lim AST, Lim TH, Tan J, Loh JL, McPherson JR, Khuntikeo N, Bhudhisawasdi V, Yongvanit P, Wongkham S, Totoki Y, Nakamura H, Arai Y, Yamasaki S, Chow PK, Chung AYF, Ooi LLPJ, Lim KH, Dima S, Duda DG, Popescu I, Broet P, Hsieh SY, Yu MC, Scarpa A, Lai J, Luo DX, Carvalho AL, Vettore AL, Rhee H, Park YN, Alexandrov LB, Gordan R, Rozen SG, Shibata T, Pairojkul C, Teh BT, Tan P. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov, 7:1116-1135, 2017

 5. Takahashi T, Elzawahry A, Mimaki S, Furukawa E, Nakatsuka R, Nakamura H, Nishigaki T, Serada S, Naka T, Hirota S, Shibata T, Tsuchihara K, Nishida T, Kato M. Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. Genes Chromosomes Cancer, 56:303-313, 2017

 6. Fukushima S, Yamashita S, Kobayashi H, Takami H, Fukuoka K, Nakamura T, Yamasaki K, Matsushita Y, Nakamura H, Totoki Y, Kato M, Suzuki T, Mishima K, Yanagisawa T, Mukasa A, Saito N, Kanamori M, Kumabe T, Tominaga T, Nagane M, Iuchi T, Yoshimoto K, Mizoguchi M, Tamura K, Sakai K, Sugiyama K, Nakada M, Yokogami K, Takeshima H, Kanemura Y, Matsuda M, Matsumura A, Kurozumi K, Ueki K, Nonaka M, Asai A, Kawahara N, Hirose Y, Takayama T, Nakazato Y, Narita Y, Shibata T, Matsutani M, Ushijima T, Nishikawa R, Ichimura K. Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas. Acta Neuropathol, 133:445-462, 2017

 7. Ohara K, Arai E, Takahashi Y, Ito N, Shibuya A, Tsuta K, Kushima R, Tsuda H, Ojima H, Fujimoto H, Watanabe SI, Katai H, Kinoshita T, Shibata T, Kohno T, Kanai Y. Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: a single-institutional methylome analysis using 1007 tissue specimens. Carcinogenesis, 38:241-251, 2017

 8. Shiokawa D, Sato A, Ohata H, Mutoh M, Sekine S, Kato M, Shibata T, Nakagama H, Okamoto K. The Induction of Selected Wnt Target Genes by Tcf1 Mediates Generation of Tumorigenic Colon Stem Cells. Cell Rep, 19:981-994, 2017

 9. Ito Y, Maeda D, Yoshida M, Yoshida A, Kudo-Asabe Y, Nanjyo H, Izumi C, Yamamoto F, Inoue M, Shibata H, Katoh H, Ishikawa S, Nakamura H, Totoki Y, Shibata T, Yachida S, Goto A. Cardiac intimal sarcoma with PDGFRbeta mutation and co-amplification of PDGFRalpha and MDM2: an autopsy case analyzed by whole-exome sequencing. Virchows Arch, 471:423-428, 2017

10. Yoshida A, Arai Y, Kobayashi E, Yonemori K, Ogura K, Hama N, Mukai W, Motoi T, Kawai A, Shibata T, Hiraoka N. CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology, 71:461-469, 2017

11. Oyama R, Takahashi M, Yoshida A, Sakumoto M, Takai Y, Kito F, Shiozawa K, Qiao Z, Arai Y, Shibata T, Araki Y, Endo M, Kawai A, Kondo T. Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines. Sci Rep, 7:4712, 2017

12. Ogura K, Hosoda F, Nakamura H, Hama N, Totoki Y, Yoshida A, Ohashi S, Rokutan H, Takai E, Yachida S, Kawai A, Tanaka S, Shibata T. Highly recurrent H3F3A mutations with additional epigenetic regulator alterations in giant cell tumor of bone. Genes Chromosomes Cancer, 56:711-718, 2017

13. Sugita S, Arai Y, Aoyama T, Asanuma H, Mukai W, Hama N, Emori M, Shibata T, Hasegawa T. NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. Hum Pathol, 65:225-230, 2017

14. Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci, 109:1282-1291, 2018

15. Hama N, Totoki Y, Miura F, Tatsuno K, Saito-Adachi M, Nakamura H, Arai Y, Hosoda F, Urushidate T, Ohashi S, Mukai W, Hiraoka N, Aburatani H, Ito T, Shibata T. Epigenetic landscape influences the liver cancer genome architecture. Nat Commun, 9:1643, 2018

16. Ohmoto A, Suzuki M, Takai E, Rokutan H, Fujiwara Y, Morizane C, Yanagihara K, Shibata T, Yachida S. Establishment of preclinical chemotherapy models for gastroenteropancreatic neuroendocrine carcinoma. Oncotarget, 9:21086-21099, 2018

17. Kawai A, Goto T, Shibata T, Tani K, Mizutani S, Nishikawa A, Matsumoto S, Nagata K, Narukawa M, Matsui S, Ando M, Toguchida J, Monden M, Heike T, Kimura S, Ueda R. Current state of therapeutic development for rare cancers in Japan, and proposals for improvement. Cancer Sci, 109:1731-1737, 2018

18. Kato M, Nakamura H, Nagai M, Kubo T, Elzawahry A, Totoki Y, Tanabe Y, Furukawa E, Miyamoto J, Sakamoto H, Matsumoto S, Sunami K, Arai Y, Suzuki Y, Yoshida T, Tsuchihara K, Tamura K, Yamamoto N, Ichikawa H, Kohno T, Shibata T. A computational tool to detect DNA alterations tailored to formalin-fixed paraffin-embedded samples in cancer clinical sequencing. Genome Med, 10:44, 2018

19. Ogura K, Hosoda F, Arai Y, Nakamura H, Hama N, Totoki Y, Yoshida A, Nagai M, Kato M, Ohashi S, Shimizu H, Arakawa E, Mukai W, Rokutan H, Kawai A, Tanaka S, Shibata T. Integrated genetic and epigenetic analysis of myxofibrosarcoma. Nat Commun, 2018

20. Udagawa C, Nakamura H, Ohnishi H, Tamura K, Shimoi T, Yoshida M, Yoshida T, Totoki Y, Shibata T, Zembutsu H. Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity. Cancer Sci, 109:446-452, 2018

21. Kataoka K, Iwanaga M, Yasunaga JI, Nagata Y, Kitanaka A, Kameda T, Yoshimitsu M, Shiraishi Y, Sato-Otsubo A, Sanada M, Chiba K, Tanaka H, Ochi Y, Aoki K, Suzuki H, Shiozawa Y, Yoshizato T, Sato Y, Yoshida K, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Shide K, Kubuki Y, Hidaka T, Nakamaki T, Ishiyama K, Miyawaki S, Ishii R, Nureki O, Tobinai K, Miyazaki Y, Takaori-Kondo A, Shibata T, Miyano S, Ishitsuka K, Utsunomiya A, Shimoda K, Matsuoka M, Watanabe T, Ogawa S. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. Blood, 131:215-225, 2018