Publications by authors named "Seishi Ogawa"

471 Publications

Whole-genome landscape of adult T-cell leukemia/lymphoma.

Blood 2021 Oct 25. Epub 2021 Oct 25.

Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, New York, United States.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors suggesting their activities in ATL. By combining the analyses for coding and non-coding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into two molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.
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http://dx.doi.org/10.1182/blood.2021013568DOI Listing
October 2021

Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of CDX2 and IDH1/2 mutations.

Blood 2021 Oct 25. Epub 2021 Oct 25.

Karolinska Institute, Sweden.

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA; 15-39 years old, n = 193) and adults (40-64 years old, n = 161) with Philadelphia chromosome-negative B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with two novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified two novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.
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http://dx.doi.org/10.1182/blood.2021011921DOI Listing
October 2021

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia.

Blood Adv 2021 Oct 18. Epub 2021 Oct 18.

Chiba Children's Hospital, Chiba, Japan.

The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. As the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMN (n = 14, 42.9%) than general population in gnomAD database (19.7%) (p = 0.042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMN was significantly higher among cases with NUDT15 variant (3.0%, 95% CI, 0.6%-9.4%) than those without (0.3%, 95% CI, 0.0-1.5%) (p = 0.045). The 6-MP dose of SMN patients with a NUDT15 variant was higher than that of those without SMN (p = 0.045). The 6-MP related mutational signature was observed in SMN specimens after 6-MP exposure. In cells under 6-MP exposure, a higher level of 6-MP-induced DNA damage in NUDT15 knockdown iPS cells. Our study indicates that NUDT15 variants may confer a risk of SMN after treatment with 6-MP among patients with ALL.
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http://dx.doi.org/10.1182/bloodadvances.2021005507DOI Listing
October 2021

Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1.

Blood Cancer Discov 2021 Sep 13;2(5):450-467. Epub 2021 Jul 13.

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

Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)-infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1-infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell-restricted (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis.

Significance: Our multimodal single-cell analyses comprehensively dissect the cellular and molecular alterations of the peripheral blood in HTLV-1 infection, with and without progression to leukemia. This study not only sheds light on premalignant clonal expansion in viral carcinogenesis, but also helps to devise novel diagnostic and therapeutic strategies for HTLV-1-related disorders.
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http://dx.doi.org/10.1158/2643-3230.BCD-21-0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514013PMC
September 2021

Maturing papillomatous nevoid melanoma in the scalp mimicking recurrent melanocytic nevus: A case report of previously undescribed subtype of nevoid melanoma.

Pathol Int 2021 Oct 12. Epub 2021 Oct 12.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Nevoid melanoma is a subtype of melanoma that histologically resembles a melanocytic nevus. Two subtypes have been proposed for nevoid melanoma, namely papillomatous and maturing. Here, we report the case of a 67-year-old woman who developed two nevoid melanomas on her scalp with composite histological features of papillomatous and maturing subtypes after electrocautery of a nearby solitary scalp papule. The histology of both lesions was very similar, papillary in shape, and both comprised two melanocyte populations, including large atypical melanocytes and small non-atypical melanocytes. Whole-exome sequencing was performed in one of the two lesions, which revealed a high mutation burden (17 mutations/megabase) with co-deletion of CDKN2A. Additional immunohistochemistry revealed that the large and small melanocytes in both lesions were completely negative for p16 and MTAP. A final diagnosis of nevoid melanoma was made. To our knowledge, this is the first report of a nevoid melanoma with both features of papillomatous and maturing subtypes. Pathologists should be aware of this subtype of melanoma to avoid misdiagnosis as a mitotically active melanocytic nevus. In this case, immunohistochemistry for p16 and MTAP, in addition to molecular analysis, helped in the final diagnosis.
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http://dx.doi.org/10.1111/pin.13178DOI Listing
October 2021

[Acquired platelet dysfunction with severe bleeding tendency in triple-negative myelofibrosis].

Rinsho Ketsueki 2021 ;62(9):1406-1411

Department of Hematology, University of Tsukuba Hospital.

A 50-year-old man demonstrated markedly increased number of white blood cells, anemia, severe splenomegaly, and bleeding tendency. Bone marrow analysis revealed remarkable hypercellularity; dysplasia in multilineage cells, including megakaryocytes; and fibrosis. He was eventually diagnosed with triple-negative myelofibrosis. A massive hematoma developed at the bone marrow biopsy site. A similar episode recurred after the second bone marrow biopsy. The von Willebrand factor and other coagulation factor activities were within normal ranges. Platelet aggregation analyses demonstrated highly impaired aggregation induced by ADP, collagen, and epinephrine. Treatment with hydroxyurea and ruxolitinib, a JAK inhibitor, was ineffective, and he eventually died on day 144 after hospitalization. Acquired platelet dysfunction uncommonly occurs in patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), without precise elucidation of the frequency and underlying mechanism. The onset of bleeding tendency in the current patient suggested that platelet dysfunction may be caused by somatic genetic events. Here, we discuss the mechanisms of acquired platelet dysfunction in MDS or MPN with a literature review.
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http://dx.doi.org/10.11406/rinketsu.62.1406DOI Listing
October 2021

Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nation-wide Consortium to Investigate Host Genetics of COVID-19.

Int J Infect Dis 2021 Sep 30. Epub 2021 Sep 30.

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Background And Design: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date.

Results: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45-71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%.

Conclusions: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.
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http://dx.doi.org/10.1016/j.ijid.2021.09.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482546PMC
September 2021

Successful treatment of hepatosplenic T-cell lymphoma with fludarabine, high-dose cytarabine and subsequent unrelated umbilical cord blood transplantation.

Int J Hematol 2021 Sep 30. Epub 2021 Sep 30.

Department of Pediatrics, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma that occurs most often in adolescents and young adults and is rare in children. Because of the aggressive clinical course, resistance to conventional chemotherapy and poor prognosis of HSTCL, an effective treatment has not been established. We report the case of a 3-year-old girl with HSTCL presenting with trilineage myelodysplasia. Although the HSTCL was refractory to conventional chemotherapy, remission was achieved with salvage chemotherapy that included fludarabine and cytarabine, which were shown to be effective in the drug sensitivity assay. After undergoing umbilical cord blood transplantation with a conditioning regimen consisting of etoposide, cyclophosphamide and total body irradiation, the patient has remained in complete remission for 8 years. Single-nucleotide polymorphism array analysis revealed heterozygous deletions of PAX5 (9p), ETV6 (12p) and homozygous deletions of CDKN2A (9p). Exome analysis showed a heterozygous nonsense c.2961C>G (p.Tyr987Ter) variant of the KMT2C gene. To improve the poor prognosis of HSTCL, the chemotherapeutic regimen can be selected for each patient on the basis of drug sensitivity and molecular genetic characteristics.
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http://dx.doi.org/10.1007/s12185-021-03229-0DOI Listing
September 2021

Genetic features of B-cell lymphoblastic lymphoma with TCF3-PBX1.

Cancer Rep (Hoboken) 2021 Sep 23:e1559. Epub 2021 Sep 23.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.

Background: Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL.

Methods: WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed.

Results: KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis.

Conclusion: In this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.
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http://dx.doi.org/10.1002/cnr2.1559DOI Listing
September 2021

Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy.

Nat Commun 2021 09 20;12(1):5547. Epub 2021 Sep 20.

Department of Urology, Keio University School of Medicine, 160-8582, Tokyo, Japan.

A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.
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http://dx.doi.org/10.1038/s41467-021-25865-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452744PMC
September 2021

The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape.

PLoS Pathog 2021 Sep 20;17(9):e1009919. Epub 2021 Sep 20.

Laboratory of Viral Interactomes, GIGA Institute, University of Liege, Liege, Belgium.

Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.
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http://dx.doi.org/10.1371/journal.ppat.1009919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483338PMC
September 2021

A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells.

Cell Rep 2021 Aug;36(8):109576

Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address:

Paraspeckles are membraneless organelles formed through liquid-liquid phase separation and consist of multiple proteins and RNAs, including NONO, SFPQ, and NEAT1. The role of paraspeckles and the component NONO in hematopoiesis remains unknown. In this study, we show histone modifier ASXL1 is involved in paraspeckle formation. ASXL1 forms phase-separated droplets, upregulates NEAT1 expression, and increases NONO-NEAT1 interactions through the C-terminal intrinsically disordered region (IDR). In contrast, a pathogenic ASXL mutant (ASXL1-MT) lacking IDR does not support the interaction of paraspeckle components. Furthermore, paraspeckles are disrupted and Nono localization is abnormal in the cytoplasm of hematopoietic stem and progenitor cells (HSPCs) derived from ASXL1-MT knockin mice. Nono depletion and the forced expression of cytoplasmic NONO impair the repopulating potential of HSPCs, as does ASXL1-MT. Our study indicates a link between ASXL1 and paraspeckle components in the maintenance of normal hematopoiesis.
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http://dx.doi.org/10.1016/j.celrep.2021.109576DOI Listing
August 2021

The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under Chemoradiotherapy.

Cancer Res 2021 Oct 19;81(19):4926-4938. Epub 2021 Aug 19.

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

Esophageal squamous cell carcinoma (ESCC) often recurs after chemoradiotherapy, and the prognosis of ESCC after chemoradiotherapy has not improved over the past few decades. The mutation process in chemoradiotherapy-resistant clones and the functional relevance of genetic alterations remain unclear. To address these problems, we performed whole-exome sequencing of 52 tumor samples from 33 patients with ESCC who received radiotherapy combined with 5-fluorouracil/platinum. In multiregion analyses of pretreatment and locally recurrent lesions from five cases, most driver gene-altered clones remained under chemoradiotherapy selection pressure, while few driver gene alterations were acquired at recurrence. The mutation signatures of recurrent ESCC, including increased deletion frequency and platinum dose-dependent base substitution signatures, were substantially different from those of primary ESCC and reflected the iatrogenic impacts of chemoradiotherapy. Single-region analysis of 28 pretreatment tumors indicated that focal copy-number gain at the locus was significantly associated with poor progression-free survival and overall survival after chemoradiotherapy. gain remained throughout the chemoradiotherapy course and potentially contributes to intrinsic resistance to chemoradiotherapy. Consistent with these findings, copy number and mRNA and protein levels in ESCC cell lines correlated positively with resistance to radiotherapy, and knockdown improved sensitivity to radiotherapy. Overall, these data characterize the clonal evolution process induced by chemoradiotherapy and clinically relevant associations for genetic alterations in ESCC. These findings increase our understanding of therapeutic resistance and support the rationale for precision chemoradiotherapy. SIGNIFICANCE: Whole-exome sequencing reveals the genetic evolution of ESCC during chemoradiotherapy, highlighting gain in pretreatment tumors as a potential marker of therapy resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0653DOI Listing
October 2021

Essential thrombocythaemia with aggressive megakaryocytosis after myelofibrotic transformation.

Hematology 2021 Dec;26(1):594-600

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, Tochigi, Japan.

Background: Among myeloproliferative neoplasms, it is often difficult to distinguish essential thrombocythaemia (ET) from prefibrotic-stage primary myelofibrosis (PMF) with thrombocytosis given their overlapping clinicopathological phenotypes.

Case Presentation: We encountered a 45-year-old male who was initially diagnosed with ET and eventually became transformed to secondary myelofibrosis 20 years later. Two distinct types of aberrant megakaryocytes were observed at diagnosis: one type characteristic of ET and the other type characteristic of PMF. With a proliferation in the bone marrow, aberrant megakaryocytes were infiltrated into the extramedullary organs and were even present in the thrombus were observed at autopsy. As a result of next-generation sequencing, the significant increase of variant allele frequency (VAF) of V617F and S34Y mutations was observed in the bone marrow cells at the final stage.

Conclusions: This patient could be recognized as an atypical case of aggressive megakaryocytosis transformed from ET.
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http://dx.doi.org/10.1080/16078454.2021.1965714DOI Listing
December 2021

Tumor heterogeneity.

Cancer Cell 2021 Aug;39(8):1015-1017

Tumor heterogeneity was traditionally considered in the genetic terms, but it has now been broadened into many more facets. These facets represent a challenge in our understanding of cancer etiology but also provide opportunity for us to understand prognosis and therapy response.
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http://dx.doi.org/10.1016/j.ccell.2021.07.009DOI Listing
August 2021

Mathematical Modeling and Mutational Analysis Reveal Optimal Therapy to Prevent Malignant Transformation in Grade II IDH-Mutant Gliomas.

Cancer Res 2021 Sep 31;81(18):4861-4873. Epub 2021 Jul 31.

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-shi, Chiba, Japan.

Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut-LGG) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDH/1p19q and IDH/1p19q) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole-exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 50 cm). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm); adjuvant therapies delayed malignant transformation in IDH/1p19q but often accelerated it in IDH/1p19q. Notably, PI3K mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDH/1p19q. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs. SIGNIFICANCE: A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0985DOI Listing
September 2021

Stratification of patients with clear cell renal cell carcinoma to facilitate drug repositioning.

iScience 2021 Jul 12;24(7):102722. Epub 2021 Jun 12.

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden.

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high heterogeneity. Stratification of ccRCC is important since distinct subtypes differ in prognosis and treatment. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Further, we developed a set of biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets. We identified four drug targets, including , essential in all the three subtypes and , exclusively essential to subtype 1. Finally, we repositioned mitotane, an FDA-approved inhibitor, to treat ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth based on experiments.
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http://dx.doi.org/10.1016/j.isci.2021.102722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253978PMC
July 2021

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

Nat Med 2021 07 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

A growing genetic tree in the soil of prostate.

Authors:
Seishi Ogawa

Cell Stem Cell 2021 07;28(7):1185-1187

Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan; Department of Molecular Hematology, Karolinska Institute, Stockholm, Sweden. Electronic address:

In this issue of Cell Stem Cell, Grossmann et al. (2021) reconstructed the developmental history of the prostate gland in a 59-year-old male by 3D tracking of somatic mutations across 319 micro-dissected specimens. It provides a genetic picture of how the human prostate gland is shaped during embryogenesis, puberty, and adult life.
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http://dx.doi.org/10.1016/j.stem.2021.06.002DOI Listing
July 2021

Proteogenomic identification of an immunogenic HLA class I neoantigen in mismatch repair-deficient colorectal cancer tissue.

JCI Insight 2021 Jul 22;6(14). Epub 2021 Jul 22.

Department of Pathology, Sapporo Medical University, Sapporo, Japan.

Although CD8+ T cells recognize neoantigens that arise from somatic mutations in cancer, only a small fraction of nonsynonymous mutations give rise to clinically relevant neoantigens. In this study, HLA class I ligandomes of a panel of human colorectal cancer (CRC) and matched normal tissues were analyzed using mass spectrometry-based proteogenomic analysis. Neoantigen presentation was rare; however, the analysis detected a single neoantigen in a mismatch repair-deficient CRC (dMMR-CRC) tissue sample carrying 3967 nonsynonymous mutations, where abundant tumor-infiltrating lymphocytes (TILs) and inflamed gene expression status were observed in the tumor microenvironment (TME). Using the HLA class I ligandome data and gene expression profiles, a set of nonmutated tumor-associated antigen (TAA) candidates was concomitantly identified. Interestingly, CD8+ TILs predominantly recognized the detected neoantigen over the array of TAA candidates. Neoantigen-reactive CD8+ TILs showed PD-1 positivity and exhibited functional and specific responses. Moreover, T cell receptor (TCR) profiling identified the sequence of the neoantigen-reactive TCR clonotype and showed its expansion in the TME. Transduction of the sequenced TCR conferred neoantigen specificity and cytotoxicity to peripheral blood lymphocytes. The proteogenomic approach revealed the antigenic and reactive T cell landscape in dMMR-CRC, demonstrating the presence of an immunogenic neoantigen and its potential therapeutic applications.
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http://dx.doi.org/10.1172/jci.insight.146356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410045PMC
July 2021

Next-generation sequencing in two cases of de novo acute basophilic leukaemia.

J Cell Mol Med 2021 07 16;25(14):7095-7099. Epub 2021 Jun 16.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34 , CD203c , CD117 , CD123dim ) and basophils (CD34 , CD203c , CD117 , CD123 ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33 , CD34 , CD123 ) and basophils (CD33 , CD34 , CD123 ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts.
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http://dx.doi.org/10.1111/jcmm.16591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278069PMC
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 Cytopenia of Undetermined Significance in a Patient with Congenital Wilms' Tumor 1 and Acquired DNMT3A Gene Mutations.

Intern Med 2021 May 29. Epub 2021 May 29.

Department of Hematology, Sumitomo Hospital, Japan.

Congenital mutations of the Wilms' tumor 1 (WT1) gene can lead to various abnormalities, including renal/gonadal developmental disorders and cardiac malformations. Although there have been many reports of somatic WT1 mutations in patients with acute myeloid leukemia and myelodysplastic syndrome, congenital WT1 mutations have not been reported in hematological disorders. We herein report a patient with early-onset clonal cytopenia of undetermined significance that was associated with a congenital mutation of WT1 and an acquired mutation of DNMT3A (encoding DNA [cytosine-5]-methyltransferase 3A).
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http://dx.doi.org/10.2169/internalmedicine.7571-21DOI Listing
May 2021

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Cancer Sci 2021 Aug 28;112(8):3338-3348. Epub 2021 Jun 28.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University, Kyoto, Japan.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.
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http://dx.doi.org/10.1111/cas.14986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353892PMC
August 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

Dramatic response to encorafenib in a patient with Erdheim-Chester disease harboring the BRAF mutation.

Am J Hematol 2021 08 26;96(8):E295-E298. Epub 2021 May 26.

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

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http://dx.doi.org/10.1002/ajh.26232DOI Listing
August 2021

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

Gastric Cancer 2021 09 7;24(5):1102-1114. Epub 2021 May 7.

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown.

Methods: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed.

Results: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression.

Conclusions: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.
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http://dx.doi.org/10.1007/s10120-021-01191-8DOI Listing
September 2021

Clonal evidence for the development of neuroblastoma with extensive copy-neutral loss of heterozygosity arising in a mature teratoma.

Cancer Sci 2021 Jul 6;112(7):2921-2927. Epub 2021 May 6.

Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
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http://dx.doi.org/10.1111/cas.14931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253283PMC
July 2021
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