Publications by authors named "Hiroko Tanaka"

160 Publications

Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis.

Nat Med 2021 Jul 8;27(7):1239-1249. Epub 2021 Jul 8.

Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.
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http://dx.doi.org/10.1038/s41591-021-01411-9DOI Listing
July 2021

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma.

Cancer Cell 2021 Jun;39(6):793-809.e8

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
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http://dx.doi.org/10.1016/j.ccell.2021.05.008DOI Listing
June 2021

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia.

Nat Commun 2021 05 14;12(1):2833. Epub 2021 May 14.

Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
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http://dx.doi.org/10.1038/s41467-021-23097-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121838PMC
May 2021

Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, , exhibited elevated expression in stroma-rich tumors, and knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed (47%) as the most commonly mutated gene, followed by (13%) and (11%). Mutations of , , and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.
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http://dx.doi.org/10.3390/cancers13040733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916565PMC
February 2021

Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma.

Blood 2021 Mar;137(11):1491-1502

Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell-type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3' untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.
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http://dx.doi.org/10.1182/blood.2020007245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976508PMC
March 2021

Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy.

Int J Hematol 2021 Jun 5;113(6):936-940. Epub 2021 Jan 5.

Department of Hematology and Oncology, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.

Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.
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http://dx.doi.org/10.1007/s12185-020-03074-7DOI Listing
June 2021

Unbiased Detection of Driver Mutations in Extramammary Paget Disease.

Clin Cancer Res 2021 Mar 15;27(6):1756-1765. Epub 2020 Dec 15.

Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.

Purpose: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and . In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing.

Experimental Design: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence hybridization.

Results: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified , and as likely driver mutations. Copy-number alteration analysis showed regions spanning as recurrently deleted, and as recurrently amplified. , and amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence analysis validated amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of amplification status was observed in some cases.

Conclusions: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3205DOI Listing
March 2021

Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia.

Blood Adv 2020 10;4(20):5165-5173

Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.
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http://dx.doi.org/10.1182/bloodadvances.2019001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594377PMC
October 2020

Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants.

Commun Biol 2020 10 16;3(1):578. Epub 2020 Oct 16.

Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.

The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.
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http://dx.doi.org/10.1038/s42003-020-01301-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567851PMC
October 2020

Comprehensive genetic analysis of pediatric germ cell tumors identifies potential drug targets.

Commun Biol 2020 09 30;3(1):544. Epub 2020 Sep 30.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively.
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http://dx.doi.org/10.1038/s42003-020-01267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528104PMC
September 2020

Fusion partner-specific mutation profiles and KRAS mutations as adverse prognostic factors in MLL-rearranged AML.

Blood Adv 2020 10;4(19):4623-4631

Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Mixed-lineage leukemia (MLL) gene rearrangements are among the most frequent chromosomal abnormalities in acute myeloid leukemia (AML). MLL fusion patterns are associated with the patient's prognosis; however, their relationship with driver mutations is unclear. We conducted sequence analyses of 338 genes in pediatric patients with MLL-rearranged (MLL-r) AML (n = 56; JPLSG AML-05 study) alongside data from the TARGET study's pediatric cohorts with MLL-r AML (n = 104), non-MLL-r AML (n = 581), and adult MLL-r AML (n = 81). KRAS mutations were most frequent in pediatric patients with high-risk MLL fusions (MLL-MLLLT10, MLL-MLLT4, and MLL-MLLT1). Pediatric patients with MLL-r AML (n = 160) and a KRAS mutation (KRAS-MT) had a significantly worse prognosis than those without a KRAS mutation (KRAS-WT) (5-year event-free survival [EFS]: 51.8% vs 18.3%, P < .0001; 5-year overall survival [OS]: 67.3% vs 44.3%, P = .003). The adverse prognostic impact of KRAS mutations was confirmed in adult MLL-r AML. KRAS mutations were associated with adverse prognoses in pediatric patients with both high-risk (MLLT10+MLLT4+MLLT1; n = 60) and intermediate-to-low-risk (MLLT3+ELL+others; n = 100) MLL fusions. The prognosis did not differ significantly between patients with non-MLL-r AML with KRAS-WT or KRAS-MT. Multivariate analysis showed the presence of a KRAS mutation to be an independent prognostic factor for EFS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.35-3.59; P = .002) and OS (HR, 1.85; 95% CI, 1.01-3.31; P = .045) in MLL-r AML. The mutation is a distinct adverse prognostic factor in MLL-r AML, regardless of risk subgroup, and is potentially useful for accurate treatment stratification. This trial was registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry (UMIN-CTR; http://www.umin.ac.jp/ctr/index.htm) as #UMIN000000511.
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http://dx.doi.org/10.1182/bloodadvances.2020002457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556160PMC
October 2020

Frequent mutations in HLA and related genes in extranodal NK/T cell lymphomas.

Leuk Lymphoma 2021 01 23;62(1):95-103. Epub 2020 Sep 23.

Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

Extranodal NK/T cell lymphomas (ENKTCLs) are aggressive Epstein-Barr virus-associated T/NK neoplasms that predominantly affect Asians. To explore the causative somatic events, we conducted a comprehensive genetic analysis of 19 ENKTCL patients by whole-genome ( = 2), whole-exome ( = 16), and targeted sequencing ( = 15). Commonly deregulated gene pathways in ENKTCLs included epigenetic modifiers (58%, 11/19) followed by human leukocyte antigens (HLAs) and related genes including , , and (32%, 6/19), and JAK-STAT pathway (26%, 5/19). Conspicuously, loss-of-function mutations in were recurrently identified in ENKTCLs (16%, 3/19). HLA protein expression was examined by immunohistochemistry in 16 patients and lower expression was associated with advanced stages at presentation ( = .007). In conclusion, the defective antigen presenting pathway is common and related to disease progression, suggesting immune escape as a pathogenic mechanism of ENKTCLs.
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http://dx.doi.org/10.1080/10428194.2020.1821011DOI Listing
January 2021

Focally Ossified Minimally Invasive Adenocarcinoma of the Lung Coexisting With Occult Pulmonary Metastases From Thyroid Cancer.

J Thorac Imaging 2020 Nov;35(6):W119-W122

Department of Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1097/RTI.0000000000000551DOI Listing
November 2020

Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets.

NPJ Precis Oncol 2020 7;4:20. Epub 2020 Jul 7.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of and . Inhibition of and in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.
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http://dx.doi.org/10.1038/s41698-020-0125-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341754PMC
July 2020

A rare case of allergic contact dermatitis caused by 3-O-ethyl-L-ascorbic acid in skin-whitening cosmetics identified under immunosuppressive therapy.

Contact Dermatitis 2020 Dec 12;83(6):520-521. Epub 2020 Oct 12.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/cod.13652DOI Listing
December 2020

Whole genome sequencing analysis identifies recurrent structural alterations in esophageal squamous cell carcinoma.

PeerJ 2020 26;8:e9294. Epub 2020 Jun 26.

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in the Asian region, including Japan. A previous study reported mutational landscape of Japanese ESCCs by using exome sequencing. However, somatic structural alterations were yet to be explored. To provide a comprehensive mutational landscape, we performed whole genome sequencing (WGS) analysis of biopsy specimens from 20 ESCC patients in a Japanese population. WGS analysis identified non-silent coding mutations of and in ESCC. We detected six mutational signatures in ESCC, one of which showed significant association with smoking status. Recurrent structural variations, many of which were chromosomal deletions, affected genes such as and in 25%-30% of tumors. Somatic copy number amplifications at (), (), and () and deletions at () were identified. Overall, these multi-dimensional view of genomic alterations improve the understanding of the ESCC development at molecular level and provides future prognosis and therapeutic implications for ESCC in Japan.
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http://dx.doi.org/10.7717/peerj.9294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323713PMC
June 2020

Landscape and function of multiple mutations within individual oncogenes.

Nature 2020 06 8;582(7810):95-99. Epub 2020 Apr 8.

Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.
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http://dx.doi.org/10.1038/s41586-020-2175-2DOI Listing
June 2020

Genomic analysis of multiple myeloma using targeted capture sequencing in the Japanese cohort.

Br J Haematol 2020 12 9;191(5):755-763. Epub 2020 May 9.

Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Japan.

Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH-CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH-associated chromosomal translocations, such as IGH-CCND2 and IGH-MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH-CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma.
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http://dx.doi.org/10.1111/bjh.16720DOI Listing
December 2020

Direct and Indirect Contributions of Executive Function to Word Decoding and Reading Comprehension in Kindergarten.

Learn Individ Differ 2019 Dec 31;76. Epub 2019 Oct 31.

Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, 401 Parnassus Ave., San Francisco, CA 94143, USA.

Extant research is increasingly recognizing the contribution of executive function (EF) to reading comprehension alongside established predictors like word decoding and oral language. The nature of the association between EF and reading comprehension is commonly investigated in older children and in those with reading impairments. However, less is known about this relationship in emerging readers in kindergarten, where word decoding and reading comprehension are highly intertwined. Moreover, a better understanding of the mechanisms by which EF influences reading comprehension is needed. The present study investigated direct contributions of EF to reading comprehension, as well as indirect contributions via word decoding in 97 kindergarteners. Results indicated that there was a significant indirect effect of EF on reading comprehension, with word decoding mediating this association. The direct contribution of EF to reading comprehension was not significant. Implications for reading instruction and intervention for early readers are discussed.
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http://dx.doi.org/10.1016/j.lindif.2019.101783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079702PMC
December 2019

Efficient Prediction of Vitamin B Deficiencies via Machine-Learning Using Routine Blood Test Results in Patients With Intense Psychiatric Episode.

Front Psychiatry 2019 20;10:1029. Epub 2020 Feb 20.

Department of Neuropsychiatry, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.

Background: Vitamin B deficiency is common worldwide and may lead to psychiatric symptoms; however, vitamin B deficiency epidemiology in patients with intense psychiatric episode has rarely been examined. Moreover, vitamin deficiency testing is costly and time-consuming, which has hampered effectively ruling out vitamin deficiency-induced intense psychiatric symptoms. In this study, we aimed to clarify the epidemiology of these deficiencies and efficiently predict them using machine-learning models from patient characteristics and routine blood test results that can be obtained within one hour.

Methods: We reviewed 497 consecutive patients, who are deemed to be at imminent risk of seriously harming themselves or others, over a period of 2 years in a single psychiatric tertiary-care center. Machine-learning models (k-nearest neighbors, logistic regression, support vector machine, and random forest) were trained to predict each deficiency from age, sex, and 29 routine blood test results gathered in the period from September 2015 to December 2016. The models were validated using a dataset collected from January 2017 through August 2017.

Results: We found that 112 (22.5%), 80 (16.1%), and 72 (14.5%) patients had vitamin B, vitamin B, and folate (vitamin B) deficiency, respectively. Further, the machine-learning models were well generalized to predict deficiency in the future unseen data, especially using random forest; areas under the receiver operating characteristic curves for the validation dataset (i.e., the dataset not used for training the models) were 0.716, 0.599, and 0.796, respectively. The Gini importance of these vitamins provided further evidence of a relationship between these vitamins and the complete blood count, while also indicating a hitherto rarely considered, potential association between these vitamins and alkaline phosphatase (ALP) or thyroid stimulating hormone (TSH).

Discussion: This study demonstrates that machine-learning can efficiently predict some vitamin deficiencies in patients with active psychiatric symptoms, based on the largest cohort to date with intense psychiatric episode. The prediction method may expedite risk stratification and clinical decision-making regarding whether replacement therapy should be prescribed. Further research includes validating its external generalizability in other clinical situations and clarify whether interventions based on this method could improve patient care and cost-effectiveness.
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http://dx.doi.org/10.3389/fpsyt.2019.01029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044238PMC
February 2020

Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations.

EBioMedicine 2020 Mar 26;53:102659. Epub 2020 Feb 26.

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Background: The tumor microenvironment can be classified into immunologically active "inflamed" tumors and inactive "non-inflamed" tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy.

Methods: We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing.

Findings: Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells.

Interpretation: Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer.

Funding: The Japan Agency for Medical Research and Development (AMED).
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http://dx.doi.org/10.1016/j.ebiom.2020.102659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048625PMC
March 2020

Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Nature 2020 01 18;577(7789):260-265. Epub 2019 Dec 18.

Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
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http://dx.doi.org/10.1038/s41586-019-1856-1DOI Listing
January 2020

Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes.

Nat Commun 2019 11 26;10(1):5386. Epub 2019 Nov 26.

Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.
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http://dx.doi.org/10.1038/s41467-019-13001-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879617PMC
November 2019

Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia.

Blood Adv 2019 10;3(20):3157-3169

Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan.

Recent advances in the genetic understanding of acute myeloid leukemia (AML) have improved clinical outcomes in pediatric patients. However, ∼40% of patients with pediatric AML relapse, resulting in a relatively low overall survival rate of ∼70%. The objective of this study was to reveal the comprehensive genetic background of pediatric AML. We performed transcriptome analysis (RNA sequencing [RNA-seq]) in 139 of the 369 patients with de novo pediatric AML who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial and investigated correlations between genetic aberrations and clinical information. Using RNA-seq, we identified 54 in-frame gene fusions and 1 RUNX1 out-of-frame fusion in 53 of 139 patients. Moreover, we found at least 258 gene fusions in 369 patients (70%) through reverse transcription polymerase chain reaction and RNA-seq. Five gene rearrangements were newly identified, namely, NPM1-CCDC28A, TRIP12-NPM1, MLLT10-DNAJC1, TBL1XR1-RARB, and RUNX1-FNBP1. In addition, we found rare gene rearrangements, namely, MYB-GATA1, NPM1-MLF1, ETV6-NCOA2, ETV6-MECOM, ETV6-CTNNB1, RUNX1-PRDM16, RUNX1-CBFA2T2, and RUNX1-CBFA2T3. Among the remaining 111 patients, KMT2A-PTD, biallelic CEBPA, and NPM1 gene mutations were found in 11, 23, and 17 patients, respectively. These mutations were completely mutually exclusive with any gene fusions. RNA-seq unmasked the complexity of gene rearrangements and mutations in pediatric AML. We identified potentially disease-causing alterations in nearly all patients with AML, including novel gene fusions. Our results indicated that a subset of patients with pediatric AML represent a distinct entity that may be discriminated from their adult counterparts. Based on these results, risk stratification should be reconsidered.
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http://dx.doi.org/10.1182/bloodadvances.2019000404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849955PMC
October 2019

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome.

Cancer Sci 2019 Oct 10;110(10):3358-3367. Epub 2019 Sep 10.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.
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http://dx.doi.org/10.1111/cas.14160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778645PMC
October 2019

Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas.

Cancer Med 2019 08 21;8(10):4565-4573. Epub 2019 Jun 21.

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Intraductal papillary mucinous neoplasm (IPMN) of pancreas has a high risk to develop into invasive cancer or co-occur with malignant lesion. Therefore, it is important to assess its malignant risk by less-invasive approach. Pancreatic juice cell-free DNA (PJD) would be an ideal material in this purpose, but genetic biomarkers for predicting malignant risk from PJD are not yet established. We here performed deep exome sequencing analysis of PJD from 39 IPMN patients with or without malignant lesion. Somatic alterations and copy number alterations (CNAs) detected in PJD were compared with the histologic grade of IPMN to evaluate their potential as a malignancy marker. Somatic mutations of KRAS, GNAS, TP53, and RNF43 were commonly detected in PJD of IPMNs, but no association with the histologic grades of IPMN was found. Instead, mutation burden was positively correlated with the histologic grade (r = 0.427, P = 0.015). We also observed frequent copy number deletions in 17p13 (TP53) and amplifications in 7q21 and 8q24 (MYC) in PJDs. The amplifications in 7q21 and 8q24 were positively correlated with the histologic grade and most prevalent in the cases of invasive carcinoma (P = 0.002 and 7/11; P = 0.011 and 6/11, respectively). We concluded that mutation burden and CNAs detected in PJD may have potential to assess the malignant progression risk of IPMNs.
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http://dx.doi.org/10.1002/cam4.2340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712468PMC
August 2019

Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling.

Leukemia 2019 12 15;33(12):2867-2883. Epub 2019 May 15.

Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.
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http://dx.doi.org/10.1038/s41375-019-0473-1DOI Listing
December 2019

Synthesis of meso-Alkyl-Substituted Norcorrole-Ni Complexes and Conversion to 5-Oxaporphyrins(2.0.1.0).

Chemistry 2019 Jun 9;25(32):7618-7622. Epub 2019 May 9.

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.

The synthesis of antiaromatic Ni -norcorroles having primary, secondary, and tertiary alkyl groups at the reactive meso-positions was attempted. Reductive coupling of a Ni -dipyrrin precursor provided Ni -meso-dihexylnorcorrole, which underwent substantial degradation on silica gel. Introduction of tert-butyl groups was unsuccessful due to the difficult preparation of the corresponding dipyrrin precursor. Meanwhile, Ni -norcorroles with isopropyl and cyclohexyl groups were isolated as stable molecules under ambient conditions. Furthermore, we found that oxidation of Ni -meso-dialkylnorcorroles with hydrogen peroxide in the presence of sodium carbonate gave Ni -5-oxaporphyrins(2.0.1.0). In contrast, oxidation of Ni -meso-dimesitylnorcorrole under the same reaction conditions gave 10-oxaporphyrin(1.1.1.0). The contrasting reactivity can be attributed to the steric congestion around the meso-positions.
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http://dx.doi.org/10.1002/chem.201901292DOI Listing
June 2019

Frequent germline mutations of in sporadic subcutaneous panniculitis-like T-cell lymphoma.

Blood Adv 2019 02;3(4):588-595

Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in , encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable-like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.
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http://dx.doi.org/10.1182/bloodadvances.2018028340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391671PMC
February 2019

Publisher Correction: Defective Epstein-Barr virus in chronic active infection and haematological malignancy.

Nat Microbiol 2019 Mar;4(3):544

Center for Stem Cell and Regenerative Medicine, Division of Advanced Biomedical Engineering Research, Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.

In the version of this Letter originally published, in the sentence beginning "The major driver role of DDX3X mutations...", the citation "Fig. 2a-f" should have been "Fig. 2". In addition, in the sentence beginning "Another finding of interest was the presence of identical driver mutations...", the citation "Fig. 3a,b and Fig. 4" should have been "Fig. 3". This has now been amended in all versions of the Letter.
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http://dx.doi.org/10.1038/s41564-019-0387-8DOI Listing
March 2019