Annual Report 2018
Division of Cancer Genomics
Tatsuhiro Shibata, Yasushi Totoki, Yasuhito Arai, Natsuko Hama, Hiromi Nakamura, Fumie Hosoda, Hirofumi Rokutan, Mihoko Adachi, Wakako Mukai, Erika Arakawa, Seri Yamagishi, Hiroe Nozaki, Machiko Watanabe, Hiroshi Chikuta
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 understand the cancer genome as heterogeneous but intervention-able "biological systems" that contribute to the pathogenesis of cancer. This Division has also been participating in an international consortium (International Cancer Genome Consortium (ICGC) and ICGC-ARGO), contributing to the core facility of the center, and developing new informatics tools for data analysis from various types of next-generation high-performance sequencers (NGS).
Research activities
Using a combination of whole-genome bisulfite, whole-genome shotgun and long-read sequencing and virus capture sequencing of a total of 373 liver cancer genomes, we identified significant correlations between epigenetic features and genetic aberration.
We performed an integrated genomic and transcriptomic analysis of the largest multi-ethnic gastric cancer cohort in the world (Japan, Korea, Vietnam, Germany, Poland, Russia, Ukraine, U.S., China, Hong Kong, Singapore). We identified more than 100 highly mutated genes that are statistically significant and selectively mutated, and made a driver gene catalog of gastric cancer containing many new ones, which is the most accurate and detailed in the world. We also performed mutational signature analysis and identified mutational signatures characterized between ethnic groups.
To find out cancer driver alterations and biomarkers for personalized therapy in biliary tract cancer (BTC), we performed whole transcriptome sequencing analyses of BTC cases. In PRELUDE (genomic screening consortium for biliary tract cancer) for the prospective study of genotype-based molecular therapy, the combination of fluorescence in situ hybridization analysis and a targeted RNA sequencing identified FGFR2 fusion genes in formalinfixed specimens of biopsy samples leading Investigator-Initiated Clinical Trials.
By our custom HTLV-1 genome capture sequencing, accurate evaluation of integration sites, copy number, rearrangements, and nucleotide variations of the virus genome in the genomes of both Adult T-cell leukemia (ATL) cells and T cells of HTLV-1 carriers has been achieved. Based on these data, early diagnosis of acute ATL has been developed.
To identify novel diagnostic fusion genes in currently undiagnosed sarcoma cases, we performed whole transcriptomic sequencing of several cases in the NCC and identified novel KMT2A fusions (YAP1-KMT2A and VIMKMT2A) in two highly malignant sarcoma of young patients. These fusions show a distinct structural feature from that of well-characterized KMT2A-X-type fusions in leukemia and may confer novel and diagnostic driver genes in a rare subtype of sarcoma.
To determine a germline contribution to anti-cancer drug sensitivity, pharmacogenomic (PGx) target panel sequencing was conducted for cases that showed adverse reactions against molecular-target therapies (Crizotinib and Afatinib) and identified several unique variations that may associate with drug sensitivity. Whole exome sequencing identified germline variations of Japanese familial pancreatic cancer cases and uncovered known and unknown risk genes for hereditary pancreatic cancer in Japanese people.
We have improved our in-house pipeline for detecting somatic structural variations (SV) in the cancer genome and achieved higher accuracy and sensitivity. A novel bioinformatic tool to extract SV signatures with a combination of the original classification of SV and non-negative matrix factorization has been developed. This tool was applied to the whole genome sequencing data of a gastric cancer cohort and elucidated seven subtypes. Currently, the correlations between this classification and other genetic alterations (somatic mutations and copy number changes) are being conducted.
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 immunegenomics) and translational research (preclinical research, liquid clinical sequencing, PGx and germline evaluation) viewpoints. Especially tighter collaboration with cancer-immunology groups by applying single cell immuneprofiling and TCR repertoire sequencing will be achieved. This division will also contribute to the development of bioinformatics tools and human resources for analyzing large cancer genomics data.
List of papers published in 2018
Journal
1. Mizugaki H, Hamada A, Shibata T, Hosoda F, Nakamura H, Okuma Y, Shukuya T, Umemura S, Horiike A, Fukui T, Kogure Y, Daga H, Urata Y, Yamada K, Saeki S, Fujisaka Y, Nakamura Y, Sato M, Yoshida T, Hotta T, Oizumi S, Fujiwara Y, Ohe Y, Fujiwara Y. Exploration of germline variants responsible for adverse events of crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer by target-gene panel sequencing. Lung Cancer, 128:20-25, 2019
2. Thomas AM, Manghi P, Asnicar F, Pasolli E, Armanini F, Zolfo M, Beghini F, Manara S, Karcher N, Pozzi C, Gandini S, Serrano D, Tarallo S, Francavilla A, Gallo G, Trompetto M, Ferrero G, Mizutani S, Shiroma H, Shiba S, Shibata T, Yachida S, Yamada T, Wirbel J, Schrotz-King P, Ulrich CM, Brenner H, Arumugam M, Bork P, Zeller G, Cordero F, Dias-Neto E, Setubal JC, Tett A, Pardini B, Rescigno M, Waldron L, Naccarati A, Segata N. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med, 25:667-678, 2019
3. Wirbel J, Pyl PT, Kartal E, Zych K, Kashani A, Milanese A, Fleck JS, Voigt AY, Palleja A, Ponnudurai R, Sunagawa S, Coelho LP, Schrotz-King P, Vogtmann E, Habermann N, Nimeus E, Thomas AM, Manghi P, Gandini S, Serrano D, Mizutani S, Shiroma H, Shiba S, Shibata T, Yachida S, Yamada T, Waldron L, Naccarati A, Segata N, Sinha R, Ulrich CM, Brenner H, Arumugam M, Bork P, Zeller G. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat Med, 25:679-689, 2019
4. Rokutan H, Abe H, Nakamura H, Ushiku T, Arakawa E, Hosoda F, Yachida S, Tsuji Y, Fujishiro M, Koike K, Totoki Y, Fukayama M, Shibata T. Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia. J Pathol, 247:494-504, 2019
5. Haruta M, Arai Y, Okita H, Tanaka Y, Takimoto T, Sugino RP, Yamada Y, Kamijo T, Oue T, Fukuzawa M, Koshinaga T, Kaneko Y. Combined Genetic and Chromosomal Characterization of Wilms Tumors Identifies Chromosome 12 Gain as a Potential New Marker Predicting a Favorable Outcome. Neoplasia, 21:117-131, 2019
6. 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
7. Anderson ND, de Borja R, Young MD, Fuligni F, Rosic A, Roberts ND, Hajjar S, Layeghifard M, Novokmet A, Kowalski PE, Anaka M, Davidson S, Zarrei M, Id Said B, Schreiner LC, Marchand R, Sitter J, Gokgoz N, Brunga L, Graham GT, Fullam A, Pillay N, Toretsky JA, Yoshida A, Shibata T, Metzler M, Somers GR, Scherer SW, Flanagan AM, Campbell PJ, Schiffman JD, Shago M, Alexandrov LB, Wunder JS, Andrulis IL, Malkin D, Behjati S, Shlien A. Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science, 361:2018
8. Kawai A, Goto T, Shibata T, Tani K, Mizutani S, Nishikawa A, Shibata T, 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
9. 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
10. Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci, 109:1282-1291, 2018
11. Saito T, Niida A, Uchi R, Hirata H, Komatsu H, Sakimura S, Hayashi S, Nambara S, Kuroda Y, Ito S, Eguchi H, Masuda T, Sugimachi K, Tobo T, Nishida H, Daa T, Chiba K, Shiraishi Y, Yoshizato T, Kodama M, Okimoto T, Mizukami K, Ogawa R, Okamoto K, Shuto M, Fukuda K, Matsui Y, Shimamura T, Hasegawa T, Doki Y, Nagayama S, Yamada K, Kato M, Shibata T, Mori M, Aburatani H, Murakami K, Suzuki Y, Ogawa S, Miyano S, Mimori K. A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer. Nat Commun, 9:2884, 2018
12. Arai E, Miura F, Totoki Y, Yamashita S, Tian Y, Gotoh M, Ojima H, Nakagawa H, Takahashi Y, Nakamura H, Hama N, Kato M, Kimura H, Suzuki Y, Ito T, Shibata T, Kanai Y. Epigenome mapping of human normal purified hepatocytes: personal epigenome variation and genome-epigenome correlation. Epigenomics, 10:955- 979, 2018
13. 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
14. Ogura K, Hosoda F, Arai Y, Nakamura H, Hama N, Totoki Y, Yoshida A, Nagai M, Kato M, Arakawa E, Mukai W, Rokutan H, Kawai A, Tanaka S, Shibata T. Integrated genetic and epigenetic analysis of myxofibrosarcoma. Nat Commun, 9:2765, 2018