Department of Bioinformatics

Mamoru Kato, Asmaa Elzawahry, Eisaku Furukawa, Joe Miyamoto, Momoko Nagai, Daichi Narushima, Hanako Ono

Introduction

The Missions of the Department of Bioinformatics are 1) bioinformatics research and its application for clinical sequencing, 2) to build new theories on cancer biology through big-data analysis and computational methods, and 3) providing bioinformatics support for experimental groups in the Center as well as other research institutions.

Research activities

hWe took charge in the bioinformatics part of the clinical sequencing project in the National Cancer Center (NCC). The bioinformatics part consists of 1) development of DNA-alteration calling programs, 2) development of medical information systems for clinical sequencing, and 3) management of the computer network for clinical sequencing.

1)We previously developed computer programs optimized for FFPE samples used in clinical sequencing. These programs detect SNV, indels, gene fusions, and copy number alterations from a large amount of data produced by the next generation sequencer (NGS). This year, we improved these computer programs enough to use them as medical appliances in clinics. We have also developed and started using a program that can detect important known variants difficult to detect in principle.

2)We developed a pipeline system for the detection of somatic and germline alterations based on tumor, and two types of normal tissue samples (matched and un-matched mixed normal). We also improved a program that integrates detected alterations with clinical information to output the Expert Panel and Primary Doctor reports. The program automatically outputs a recommendation for molecularly-targeted drugs suitable for detected alterations. Those recommendations are checked by the Tumor Board and then given to primary doctors. Furthermore, we have started developing a system that electronically connects the flow from orders in the Hospital reception to the report output, and further connects them with electronic medical records.

3)We managed a cluster machine and constructed a computer network for clinical sequencing in the NCC Central Hospital. We managed hardware failure and computer/network loads.

hWe are trying to find biomarkers which are usable in clinical sequencing. We used multi-omics big data to identify genomic biomarkers for immune checkpoint expression genes in bile duct cancer, and are assessing the significance of the identified biomarkers that can be used to select patients who might get benefit from treatment using immune checkpoint therapy.

hWe performed single-cell sequencing to reveal intra-tumor heterogeneity and cancer-cell evolution, collaborating with the Division of Cancer Genomics and Chiba Cancer Center. Using a mouse model for cancer development, we performed single-cell exome and transcriptome sequencing, and developed pipeline programs to analyze the dynamics of cancer-cell subpopulations along the time-course. We quantified the expression and mutation diversity, and visualized the heterogeneity change with tumor development.

hCancer drug resistance is considered as results of cancer-cell evolution. To reveal this phenomenon, we analyzed whole-exome and transcriptome data on imatinib resistance in gastrointestinal stromal tumour (GIST). This work was done in collaboration with the NCC Hospital East and Osaka University. We revealed the evolutionary changes and found importance of variants associated with apoptosis, which suggests that apoptosis-resistant cells may have been ancestors of descendants with full resistance to imatinib treatment.

hWe provided bioinformatics analysis supports for such projects as follows:

1)T-cell RNA-Seq, methylome analysis of sarcoma, data analysis of PanCancer, and quality check of whole genome sequencing for the Division of Cancer Genomics

2)Single cell sequencing for the Division of Cancer Differentiation

3)Non coding RNA analysis for the Division of Clinical Genome Research at Chiba Cancer Center

4)CNA analysis of JCOG data

5)Variants detection of samples in the digestive system for the Clinical Pathology in the NCC Central Hospital

6)Whole genome sequencing of rats and DNA adductome analysis for the Division of Carcinogenesis and Prevention.

Education

Our department employed one researcher this year and educated her through on-the-job training. Our department gave advice to bioinformatics technical staff in the Division of Cancer Genomics.

Future prospects

We will develop bioinformatics technologies for clinical sequencing and apply them to realize precision medicine. We will analyze medical big data to find novel tumor molecular markers and subtypes that are applicable to clinical sequencing. We will promote single-cell sequencing and theoretical studies to reveal cancer-cell evolution. We will keep continue to provide bioinformatics support for other groups in the Center and other institutions.

List of papers published in 2016

Journal

1.Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y, Tanaka H, Taniguchi H, Kawakami Y, Ueno M, Gotoh K, Ariizumi S, Wardell CP, Hayami S, Nakamura T, Aikata H, Arihiro K, Boroevich KA, Abe T, Nakano K, Maejima K, Sasaki-Oku A, Ohsawa A, Shibuya T, Nakamura H, Hama N, Hosoda F, Arai Y, Ohashi S, Urushidate T, Nagae G, Yamamoto S, Ueda H, Tatsuno K, Ojima H, Hiraoka N, Okusaka T, Kubo M, Marubashi S, Yamada T, Hirano S, Yamamoto M, Ohdan H, Shimada K, Ishikawa O, Yamaue H, Chayama K, Miyano S, Aburatani H, Shibata T, Nakagawa H. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet, 48:500-509, 2016

2.Yachida S, Wood LD, Suzuki M, Takai E, Totoki Y, Kato M, Luchini C, Arai Y, Nakamura H, Hama N, Elzawahry A, Hosoda F, Shirota T, Morimoto N, Hori K, Funazaki J, Tanaka H, Morizane C, Okusaka T, Nara S, Shimada K, Hiraoka N, Taniguchi H, Higuchi R, Oshima M, Okano K, Hirono S, Mizuma M, Arihiro K, Yamamoto M, Unno M, Yamaue H, Weiss MJ, Wolfgang CL, Furukawa T, Nakagama H, Vogelstein B, Kiyono T, Hruban RH, Shibata T. Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma. Cancer Cell, 29:229-240, 2016

3.Uchi R, Takahashi Y, Niida A, Shimamura T, Hirata H, Sugimachi K, Sawada G, Iwaya T, Kurashige J, Shinden Y, Iguchi T, Eguchi H, Chiba K, Shiraishi Y, Nagae G, Yoshida K, Nagata Y, Haeno H, Yamamoto H, Ishii H, Doki Y, Iinuma H, Sasaki S, Nagayama S, Yamada K, Yachida S, Kato M, Shibata T, Oki E, Saeki H, Shirabe K, Oda Y, Maehara Y, Komune S, Mori M, Suzuki Y, Yamamoto K, Aburatani H, Ogawa S, Miyano S, Mimori K. Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution. PLoS Genet, 12:e1005778, 2016

4.Ichimura K, Fukushima S, Totoki Y, Matsushita Y, Otsuka A, Tomiyama A, Niwa T, Takami H, Nakamura T, Suzuki T, Fukuoka K, Yanagisawa T, Mishima K, Nakazato Y, Hosoda F, Narita Y, Shibui S, Yoshida A, Mukasa A, Saito N, Kumabe T, Kanamori M, Tominaga T, Kobayashi K, Shimizu S, Nagane M, Iuchi T, Mizoguchi M, Yoshimoto K, Tamura K, Maehara T, Sugiyama K, Nakada M, Sakai K, Kanemura Y, Nonaka M, Asai A, Yokogami K, Takeshima H, Kawahara N, Takayama T, Yao M, Kato M, Nakamura H, Hama N, Sakai R, Ushijima T, Matsutani M, Shibata T, Nishikawa R. Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta Neuropathol, 131:889-901, 2016

5.Tanabe Y, Ichikawa H, Kohno T, Yoshida H, Kubo T, Kato M, Iwasa S, Ochiai A, Yamamoto N, Fujiwara Y, Tamura K. Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials. Mol Cancer, 15:73, 2016