Human Genome Center Laboratory of DNA Information Analysis Laboratory of Sequence ... ·...

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1. Pan-Cancer Analysis of Whole Genomes

Pan-Cancer Analysis of Whole Genomes Consorti-um (Collaborators (1341)

Cancer is driven by genetic change, and the ad-vent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. 1341 collaborators worked for the integrative analysis of 2,658 whole-cancer ge-nomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of

the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer ge-nomes contained 4-5 driver mutations when combin-ing coding and non-coding genomic elements; how-ever, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several can-cer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to criti-

Human Genome Center

Laboratory of DNA Information AnalysisLaboratory of Sequence AnalysisLaboratory of Genome DatabaseDNA情報解析分野シークエンスデータ情報処理分野ゲノムデータベース分野

Professor Satoru Miyano, Ph.D.Assistant Professor Yao-zhong Zhang, Ph.D.Associate Professor Tetsuo Shibuya, Ph.D.Assistant Professor Kotoe Katayama, Ph.D.Project Assistant Professor Taku Onodera, Ph.D.

教　授　　理学博士　　　　宮　野　　　悟助　教　　博士（情報理工学）　Yao-zhong Zhang准教授　　博士（理学）　　　渋　谷　哲　朗助　教　　博士（工学）　　　片　山　琴　絵特任助教　博士（情報理工学）　小　野　寺　拓

We are facing with biomedical big data comprising of ultra-high dimensional ultra-heterogeneous data. Our current mission is to develop computational/informatics strategy for medical informatics to implement personalized genomic medicine through genomics, systems biology and supercomputer.

●Annual Report.indb 55●Annual Report.indb 55 2020/05/22 10:48:542020/05/22 10:48:54

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cal levels. Common and rare germline variants affect patterns of somatic mutation, including point muta-tions, structural variants and somatic retrotransposi-tion. A collection of papers from the PCAWG Consor-tium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcrip-tional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes

The supercomputer SHIROKANE of Human Ge-nome Center performed computational analyses as one of the six centers for this project.

2. Systems Cancer Research and Systems Biolo-gy

a. Divergent lncRNA MYMLR regulates MYC by eliciting DNA looping and promoter-enhancer interaction

Kajino T1, Shimamura T1, Gong S1, Yanagisawa K1, Ida L1, Nakatochi M1, Griesing S1, Shimada Y1, Kano K1, Suzuki M1, Miyano S, Takahashi T1,2; 1Na-goya University, 2Aichi Cancer Center

Long non-coding RNAs (lncRNAs) function in a wide range of processes by diverse mechanisms, though their roles in regulation of oncogenes and/or tumor suppressors remain rather elusive. We per-formed a global search for lncRNAs affecting MYC activity using a systems biology-based approach with a K supercomputer and the GIMLET algorism based on local distance correlations. Consequently, MYMLR was identified and experimentally shown to maintain MYC transcriptional activity and cell cycle progres-sion despite the low levels of expression. A proteomic search for MYMLR-binding proteins identified PCBP2, while it was also found that MYMLR places a 557-kb upstream enhancer region in the proximity of the MYC promoter in cooperation with PCBP2. These findings implicate a crucial role for MYMLR in regu-lation of the archetypical oncogene MYC and warrant future studies regarding the involvement of low copy number lncRNAs in regulation of other crucial onco-genes and tumor suppressor genes.

K computer at RIKEN performed the data analy-sis.

b. Virtual Grid Engine: a simulated grid engine environment for large-scale supercomputers

Ito S, Yadome M, Nishiki T3, Ishiduki S3, Inoue H3, Yamaguchi R2, Miyano S; 3Fujitsu Limited

Supercomputers have become indispensable in-

frastructures in science and industries. In particular, most state-of-the-art scientific results utilize massive-ly parallel supercomputers ranked in TOP500. How-ever, their use is still limited in the bioinformatics field due to the fundamental fact that the asynchro-nous parallel processing service of Grid Engine is not provided on them. To encourage the use of massively parallel supercomputers in bioinformatics, we devel-oped middleware called Virtual Grid Engine, which enables software pipelines to automatically perform their tasks as MPI programs.

We conducted basic tests to check the time re-quired to assign jobs to workers by VGE. The results showed that the overhead of the employed algorithm was 246 microseconds and our software can manage thousands of jobs smoothly on the K computer. We also tried a practical test in the bioinformatics field. This test included two tasks, the split and BWA align-ment of input FASTQ data. 25,055 nodes (2,000,440 cores) were used for this calculation and accom-plished it in three hours.

We considered that there were four important re-quirements for this kind of software, non-privilege server program, multiple job handling, dependency control, and usability. We carefully designed and checked all requirements. And this software fulfilled all the requirements and achieved good performance in a large scale analysis.

c. A Bayesian model integration for mutation calling through data partitioning

Moriyama T, Imoto S4, Hayashi S, Shiraishi Y5, Mi-yano S, Yamaguchi R; 4Health Intelligence Center, 5National Cancer Center

Detection of somatic mutations from tumor and matched normal sequencing data has become among the most important analysis methods in cancer re-search. Some existing mutation callers have focused on additional information, e.g. heterozygous sin-gle-nucleotide polymorphisms (SNPs) nearby muta-tion candidates or overlapping paired-end read infor-mation. However, existing methods cannot take multiple information sources into account simultane-ously. Existing Bayesian hierarchical model-based methods construct two generative models, the tumor model and error model, and limited information sources have been modeled.

We proposed a Bayesian model integration frame-work named as partitioning-based model integration. In this framework, through introducing partitions for paired-end reads based on given information sources, we integrate existing generative models and utilize multiple information sources. Based on that, we con-structed a novel Bayesian hierarchical model-based method named as OHVarfinDer. In both the tumor model and error model, we introduced partitions for a set of paired-end reads that cover a mutation candi-


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date position, and applied a different generative model for each category of paired-end reads. We demonstrated that our method can utilize both hete-rozygous SNP information and overlapping paired-end read information effectively in simulation data-sets and real datasets. The software application is available from https: //github.com/takumorizo/OHV arfinDer.

d. Accurate and flexible Bayesian mutation call from multi-regional tumor samples

Moriyama T, Imoto S4, Miyano S, Yamaguchi R2

We propose a Bayesian method termed MultiMuC for accurate detection of somatic mutations (mutation call) from multi-regional tumor sequence data sets. To improve detection performance, our method is based on the assumption of mutation sharing: if we can predict at least one tumor region has the muta-tion, then we can be more confident to detect a muta-tion in more tumor regions by lowering the original threshold of detection. We find two drawbacks in ex-isting methods for leveraging the assumption of mu-tation sharing. First, existing methods do not consider the probability of the “No-TP (True Positive)” case: we could expect mutation candidates in multiple regions, but actually, no true mutations exist. Second, existing methods cannot leverage scores from other state-of-the-art mutation calling methods for a single-regional tumor. We overcome the first drawback through eval-uation of the probability of the No-TP case. Next, we solve the second drawback by the idea of Bayes-fac-tor-based model construction that enables flexible in-tegration of probability-based mutation call scores as building blocks of a Bayesian statistical model. We empirically evaluate that our method steadily im-proves results from mutation calling methods for a single-regional tumor, e.g., Strelka2 and NeuSomatic, and outperforms existing methods for multi-regional tumors through a real-data-based simulation study. Our implementation of MultiMuC is available at https: //github.com/takumorizo/MultiMuC.

e. ALPHLARD-NT: Bayesian method for human leukocyte antigen genotyping and mutation calling through simultaneous analysis of nor-mal and tumor whole-genome sequence data

Hayashi S, Moriyama T, Yamaguchi R, Mizuno S6, Komura M, Miyano S, Nakagawa H7, Imoto S4; 6Kyusu University, 7RIKEN

Human leukocyte antigen (HLA) genes provide useful information on the relationship between can-cer and the immune system. Despite the ease of ob-taining these data through next-generation sequenc-ing methods, interpretation of these relationships remains challenging owing to the complexity of HLA

genes. To resolve this issue, we developed a Bayesian method, ALPHLARD-NT, to identify HLA germline and somatic mutations as well as HLA genotypes from whole-exome sequencing (WES) and whole-ge-nome sequencing (WGS) data. ALPHLARD-NT showed 99.2% accuracy for WGS-based HLA geno-typing and detected five HLA somatic mutations in 25 colon cancer cases. In addition, ALPHLARD-NT identified 88 HLA somatic mutations, including re-current mutations and a novel HLA-B type, from WES data of 343 colon adenocarcinoma cases. These results demonstrate the potential of ALPHLARD-NT for conducting an accurate analysis of HLA genes even from low-coverage data sets. This method can become an essential tool for comprehensive analyses of HLA genes from WES and WGS data, helping to advance understanding of immune regulation in can-cer as well as providing guidance for novel immuno-therapy strategies.

3. Cancer Genomicsa. Frequent mutations that converge on the NFK-

BIZ pathway in ulcerative colitis

Kakiuchi N8, Yoshida K8, Uchino M9, Kihara T9, Akaki K8, Inoue Y8, Kawada K8, Nagayama S10, Yokoyama A8, Yamamoto S8, Matsuura M8, Hori-matsu T8, Hirano T8, Goto N8, Takeuchi Y8, Ochi Y8, Shiozawa Y8, Kogure Y8, Watatani Y8, Fujii Y8, Kim SK8, Kon A8, Kataoka K8, Yoshizato T8, Nakagawa MM8, Yoda A8, Nanya Y8, Makishima H8, Shiraishi Y5, Chiba K5, Tanaka H, Sanada M8, Sugihara E11, Sato TA11, Maruyama T12, Miyoshi H8, Taketo MM8, Oishi J13, Inagaki R8, Ueda Y13, Okamoto S8, Okaji-ma H8, Sakai Y8, Sakurai T8, Haga H8, Hirota S9, Ikeuchi H9, Nakase H8, Marusawa H8, Chiba T8, Takeuchi O8, Miyano S, Seno H8, Ogawa S8,14; 8Kyo-to University, 9Hyogo College of Medicine, 10Japa-nese Foundation for Cancer Research, 11University of Tsukuba, 12Akita University, 13Sumitomo Dainip-pon Pharma, 14Karolinska Institute

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol con-sumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and in-crease their number and size with ageing, and ulti-mately replace almost the entire oesophageal epitheli-um in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D muta-tions in physiologically normal oesophageal epithe-


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lia; these mutations can be acquired before late ado-lescence (as early as early infancy) and significantly increase in number with heavy smoking and drink-ing. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Our DNA and RNA-sequence analysis pipe line Genomon (https: //github.com/Genomon-Project) on HGC supercomputer SHIROKANE played an impor-tant role in this study. We contributed to sequence data analysis and statistical methodology develop-ment using HGC supercomputer SHIROKANE.

b. Defective Epstein-Barr virus in chronic active infection and haematological malignancy

Okuno Y15, Murata T16, Sato Y16, Muramatsu H16, Ito Y16, Watanabe T16, Okuno T16, Murakami N16, Yoshida K8, Sawada A17, Inoue M17, Kawa K17, Seto M18, Ohshima K18, Shiraishi Y5, Chiba K5, Tanaka H, Miyano S, Narita Y16, Yoshida M16, Goshima F16, Kawada JI16, Nishida T16, Kiyoi H16, Kato S15, Naka-mura S15, Morishima S19, Yoshikawa T20, Fujiwara S21, Shimizu N22, Isobe Y23, Noguchi M24, Kikuta A25, Iwatsuki K26, Takahashi Y16, Kojima S16, Ogawa S8, Kimura H16; 15Nagoya University Hospital, 16Nagoya University Graduate School of Medicine, 17Osaka Women’s and Children’s Hospital, 18Kurume Uni-versity School of Medicine, 19University of the Ryukyus, 20Fujita Health University School of Med-icine, 21National Research Institute for Child Health and Development 22Tokyo Medical and Dental Uni-versity, 23St. Marianna University School of Medi-cine, 24Juntendo University Urayasu Hospital, 25Fukushima Medical University School of Medi-cine, 26Okayama University Graduate School of Medicine

Epstein-Barr virus (EBV) infection is highly preva-lent in humans and is implicated in various diseases, including cancer. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lym-phoproliferative disorder in the 2016 World Health Organization lymphoma classification. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleo-sis-like symptoms. Here, we show that CAEBV origi-nates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspic-uously, the EBV genome in CAEBV patients har-boured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lym-phoma, but were not detected in infectious mononu-cleosis or post-transplant lymphoproliferative disor-ders (0/47), which suggests a unique role of these

mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing vi-ral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by up-regulating the expression of two immediate early genes, BZLF1 and BRLF1, while averting viral pro-duction and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in up-regulation of the lytic cycle and the promotion of lym-phomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic prolifera-tions.

Our DNA and RNA-sequence analysis pipe line Genomon on HGC supercomputer SHIROKANE played an important role in this study. We contribut-ed to sequence data analysis and statistical methodol-ogy development using HGC supercomputer SHI-ROKANE.

c. Applications of Genomon for Cancer Genom-ics

All laboratory members and many collaborators

We have been developing an omics analysis pipe-line Genomon for analyzing genome sequence data including RNA sequences. By collaborations with many cancer researchers, we contributed to data anal-yses using the supercomputer at Human Genome Center and K computer at RIKEN. Due to the limit of space, we list up our contributed papers: 2-3, 5, 8-11, 14, 20-24, 26, 28-32, 34, 36, 39, 43-47.

4. Contributions by System for Cancer Clinical Sequencing

We have developed a system for cancer clinical se-quencing using HGC supercomputer and Genomon, and have been contributing to cancer genomic medi-cine at IMSUT Research Hospital.

a. Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS

Nakamura S27, Yokoyama K27, 28, Shimizu E, Yusa N28, Kondoh K27, Ogawa M27, Takei T27, Kobayashi A27, Ito M27, Isobe M27, 28, Konuma T28, Kato S28, Kasajima R4, Wada Y28, Nagamura-Inoue T6, Yama-guchi R, Takahashi S27, 28, Imoto S4, Miyano S, Tojo A27, 28; 27Advanced Clinical Research Center, 28Re-search Hospital

This study was performed to assess the utility of tumor-derived fragmentary DNA, or circulating tu-mor DNA (ctDNA), for identifying high-risk patients


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for relapse of acute myeloid leukemia and myelodys-plastic syndrome (AML/MDS) after undergoing mye-loablative allogeneic hematopoietic stem cell trans-plantation (alloSCT). We retrospectively collected tumor and available matched serum samples at diag-nosis and 1 and 3 months post-alloSCT from 53 pa-tients with AML/MDS. After identifying driver muta-tions in 51 patients using next-generation sequencing, we designed at least 1 personalized digital polymer-ase chain reaction assay per case. Diagnostic ctDNA and matched tumor DNA exhibited excellent correla-tions with variant allele frequencies. Sixteen patients relapsed after a median of 7 months post-alloSCT. Both mutation persistence (MP) in bone marrow (BM) at 1 and 3 months post-alloSCT and corresponding ctDNA persistence (CP) in the matched serum (MP1 and MP3; CP1 and CP3, respectively) were compara-bly associated with higher 3-year cumulative inci-dence of relapse (CIR) rates (MP1 vs non-MP1, 72.9% vs 13.8% [P = .0012]; CP1 vs non-CP1, 65.6% vs 9.0% [P = .0002]; MP3 vs non-MP3, 80% vs 11.6% [P = .0002]; CP3 vs non-CP3, 71.4% vs 8.4% [P < .0001]). We subsequently evaluated whether subset analysis of patients with 3 genes associated with clonal he-matopoiesis, DNMT3A, TET2, and ASXL1 (DTA), could also be helpful in relapse prediction. As a re-sult, CP based on DTA gene mutations also had the prognostic effect on CIR. These results, for the first time, support the utility of ctDNA as a noninvasive prognostic biomarker in patients with AML/MDS un-dergoing alloSCT.

b. The first case of elderly TCF3-HLF-positive B-cell acute lymphoblastic leukemia

Takeda R27,28, Yokoyama K28, Ogawa M27, Kawama-ta T28, Fukuyama T27,28 Kondoh K27,28, Takei T27, Na-kamura S27, Ito M27, Yusa N28, Shimizu E, Ohno N30, Uchimaru K27,29, Yamaguchi R, Imoto S4, Miyano S, Tojo A27,28; 29Graduate School of Frontier Sciences, 30Kanto Rosai Hospital

A 67-year-old man, who complained of persistent fever and general fatigue, was referred to our hospi-tal. Peripheral blood examination showed that white blood cell (WBC) count was elevated to 9.2 × 109/L, with 27.5% myeloperoxidase-negative blasts. Anemia (hemoglobin, 9.2 g/dL) and thrombocytopenia (plate-lets, 43 × 109/L) were also observed. Lactate dehydro-genase was elevated to approximately four times the upper normal limit. The patient also presented with severe DIC, hypercalcemia, and mild renal dysfunc-tion. Computed tomography (CT) revealed mild gen-eralized lymphadenopathy without hepatospleno-megaly and osteolytic changes in bones. Bone marrow (BM) aspiration showed infiltration of myeloperoxi-dase-negative blasts in 86% of the counted nuclear cells. Flowcytometric analysis showed that these blast cells were positive for CD10, CD19, cytoplasmic

CD79a, TdT, CD13, CD33, and HLA-DR. Cytogenetic analysis identified the chromosomal translocation t(17; 19)(q22; p13). Transcription of chimeric TCF3-HLF in leukemia cells was detected by reverse tran-scription polymerase chain reaction (RT-PCR). Hence, the patient was diagnosed with TCF3-HLF-positive B-ALL. He initially received standard chemotherapy for adult B-ALL, containing daunorubicin, cyclophos-phamide, vincristine (VCR), L-asparaginase, and prednisolone. After the chemotherapy was adminis-tered, the leukemia cell count decreased rapidly, ac-companied by amelioration of DIC and hypercalce-mia. However, the response was transient, resulting in primary induction failure. The leukemia cells re-grew with exacerbation of the complications. Four additional lines of conventional chemotherapies also failed to achieve durable remission. Thus, this case of leukemia appeared refractory to agents including glucocorticoids, L-asparaginase, anthracyclines, cy-clophosphamide, VCR, cytarabine (Ara-C), etopo-side, and methotrexate (MTX). At the end of the fifth chemotherapy, the patient lost consciousness due to intracerebral hemorrhage, followed by drastic growth of the leukemia cells and DIC. The patient died of leu-kemia five months after the initial diagnosis.

c. Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP pa-tient

Yamaguchi K27, Shimizu E, Yamaguchi R, Imoto S4, Komura M, Hatakeyama S27, Noguchi R27, Takane K27, Ikenoue T27, Gohda Y31, Yano H31, Miyano S, Furukawa Y27; 31National Center for Global Health and Medicine,

Polymerase proofreading-associated polyposis (PPAP) is a disease caused by germline variations in the POLE and POLD1 genes that encode catalytic sub-units of DNA polymerases. Studies of cancer genomes have identified somatic mutations in these genes, sug-gesting the importance of polymerase proofreading of DNA replication in suppressing tumorigenesis. Here, we identified a germline frameshift variation in the POLE gene (c.4191_4192delCT, p.Tyr1398*) in a case with multiple adenomatous polyps and three synchronous colon cancers. Interestingly, one of the colon cancers showed microsatellite instability-high (MSI-H) and another microsatellite stable. Immuno-histochemical staining revealed that the MSI-H tumor cells lost the expression of MLH1 protein. Whole ge-nome sequencing of the MSI-H tumor did not find pathogenic somatic mutations in mismatch repair genes but found frameshift mutations in the TET genes that catalyze 5-methylcytosine hydroxylation. Bisulfite sequencing of the tumor corroborated an in-crease in the number of hypermethylated regions in-cluding the MLH1 promoter. These data indicate that PPAP patients might develop MSI-positive tumors


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through epigenetic silencing of MLH1. These findings will contribute to comprehensive understanding of

the molecular basis of tumors that involve deficiency of proofreading activity of DNA polymerases.

Publications

1. ICGC/TCGA Pan-Cancer Analysis of Whole Ge-nomes Consortium (Collaborators (1341)). Pan-can-cer analysis of whole genomes. Nature. 2020; 578(7793): 82-93.

2. Kasajima R, Yamaguchi R, Shimizu E, Tamada Y, Niida A, Tremmel G, Kishida T,Aoki I, Imoto S, Mi-yano S, Uemura H, Miyagi Y. Variant analysis of prostate cancer in Japanese patients and a new at-tempt to predict related biological pathways. Oncol Rep. 2020; 43(3): 943-952.

3. Kakiuchi N, Yoshida K, Uchino M, Kihara T, Akaki K, Inoue Y, Kawada K, Nagayama S, Yokoyama A, Yamamoto S, Matsuura M, Horimatsu T, Hirano T, Goto N, Takeuchi Y, Ochi Y, Shiozawa Y, Kogure Y, Watatani Y, Fujii Y, Kim SK, Kon A, Kataoka K, Yoshizato T, Nakagawa MM, Yoda A, Nanya Y, Makishima H, Shiraishi Y, Chiba K, Tanaka H, San-ada M, Sugihara E, Sato TA, Maruyama T, Miyoshi H, Taketo MM, Oishi J, Inagaki R, Ueda Y, Okamo-to S, Okajima H, Sakai Y, Sakurai T, Haga H, Hirota S, Ikeuchi H, Nakase H, Marusawa H, Chiba T, Takeuchi O, Miyano S, Seno H, Ogawa S. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature. 2020; 577(7789): 260-265.

4. Hirata M, Asano N, Katayama K, Yoshida A, Tsuda Y, Sekimizu M, Mitani S, Kobayashi E, Komiyama M, Fujimoto H, Goto T, Iwamoto Y, Naka N, Iwata S, Nishida Y, Hiruma T, Hiraga H, Kawano H, Mo-toi T, Oda Y, Matsubara D, Fujita M, Shibata T, Na-kagawa H, Nakayama R, Kondo T, Imoto S, Miyano S, Kawai A, Yamaguchi R, Ichikawa H, Matsuda K. Integrated exome and RNA sequencing of dediffer-entiated liposarcoma. Nat Commun. 2019; 10(1): 5683. Publisher Correction: Nat Commun. 2020; 11(1): 1024.

5. Taguchi M, Mishima H, Shiozawa Y, Hayashida C, Kinoshita A, Nannya Y, Makishima H, Horai M, Matsuo M, Sato S, Itonaga H, Kato T, Taniguchi H, Imanishi D, Imaizumi Y, Hata T, Takenaka M, Mo-riuchi Y, Shiraishi Y, Miyano S, Ogawa S, Yoshiura KI, Miyazaki Y. Genome analysis of myelodysplas-tic syndromes among atomic bomb survivors in Nagasaki. Haematologica. 2020; 105(2): 358-365.

6. Ito S, Yadome M, Nishiki T, Ishiduki S, Inoue H, Yamaguchi R, Miyano S. Virtual Grid Engine: a simulated grid engine environment for large-scale supercomputers. BMC Bioinformatics. 2019; 20(Sup-pl 16): 591.

7. Moriyama T, Imoto S, Miyano S, Yamaguchi R. Ac-curate and flexible Bayesian mutation call from multi-regional tumor samples. LNCS 2019; 11826: 47-61.

8. Nagata Y, Makishima H, Kerr CM, Przychodzen BP, Aly M, Goyal A, Awada H, Asad MF, Kuz-manovic T, Suzuki H, Yoshizato T, Yoshida K, Chi-ba K, Tanaka H, Shiraishi Y, Miyano S, Mukherjee S, LaFramboise T, Nazha A, Sekeres MA, Radi-voyevitch T, Haferlach T, Ogawa S, Maciejewski JP. Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syn-dromes. Nat Commun. 2019; 10(1): 5386.

9. Kimura S, Seki M, Kawai T, Goto H, Yoshida K, Iso-be T, Sekiguchi M, Watanabe K, Kubota Y, Nannya Y, Ueno H, Shiozawa Y, Suzuki H, Shiraishi Y, Ohki K, Kato M, Koh K, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Manabe A, Sanada M, Mansour MR, Ohara A, Horibe K, Kobayashi M, Oka A, Hayashi Y, Miyano S, Hata K, Ogawa S, Takita J. DNA methylation-based classifi-cation reveals difference between pediatric T-cell acute lymphoblastic leukemia and normal thymo-cytes. Leukemia. 2019 Nov 15. doi: 10.1038/s41375-019-0626-2. [Epub ahead of print]

10. Takeda R, Yokoyama K, Kobayashi S, Kawamata T, Nakamura S, Fukuyama T, Ito M, Yusa N, Shimizu E, Ohno N, Yamaguchi R, Imoto S, Mi-yano S, Uchimaru K, Tojo A. An unusually short latent period of therapy-related myeloid neoplasm harboring a rare MLL-EP300 rearrangement: case report and literature review. Case Rep Hematol. 2019; 2019: 4532434.

11. Shiba N, Yoshida K, Hara Y, Yamato G, Shiraishi Y, Matsuo H, Okuno Y, Chiba K, Tanaka H, Kaburagi T, Takeuchi M, Ohki K, Sanada M, Okubo J, Tom-izawa D, Taki T, Shimada A, Sotomatsu M, Horibe K, Taga T, Adachi S, Tawa A, Miyano S, Ogawa S, Hayashi Y. Transcriptome analysis offers a com-prehensive illustration of the genetic background of pediatric acute myeloid leukemia. Blood Adv. 2019; 3(20): 3157-3169.

12. Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Tsuch-ida R, Hino S, Sakamoto A, Igarashi K, Saitoh K, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibu-chi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T. Phos-phoethanolamine accumulation protects cancer cells under glutamine starvation through down-regulation of PCYT2. Cell Rep. 2019; 29(1): 89-103.e7.

13. Matsuno Y, Atsumi Y, Shimizu A, Katayama K, Fujimori H, Hyodo M, Minakawa Y, Nakatsu Y, Kaneko S, Hamamoto R, Shimamura T, Miyano S,


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Tsuzuki T, Hanaoka F, Yoshioka KI. Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vit-ro. Nat Commun. 2019; 10(1): 3925.

14. Kubota Y, Uryu K, Ito T, Seki M, Kawai T, Isobe T, Kumagai T, Toki T, Yoshida K, Suzuki H, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Ohki K, Ki-yokawa N, Kagawa J, Miyano S, Oka A, Hayashi Y, Ogawa S, Terui K, Sato A, Hata K, Ito E, Takita J. Integrated genetic and epigenetic analysis re-vealed heterogeneity of acute lymphoblastic leu-kemia in Down syndrome. Cancer Sci. 2019; 110(10): 3358-3367.

15. Kajino T, Shimamura T, Gong S, Yanagisawa K, Ida L, Nakatochi M, Griesing S, Shimada Y, Kano K, Suzuki M, Miyano S, Takahashi T. Divergent ln-cRNA MYMLR regulates MYC by eliciting DNA looping and promoter-enhancer interaction. EMBO J. 2019; 38(17): e98441.

16. Yoshino T, Katayama K, Yamaguchi R, Imoto S, Miyano S, Mima H, Watanabe K. Classification of patients with cold sensation by a review of sys-tems database: A single-centre observational study. Complement Ther Med. 2019; 45: 7-13.

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