Publications by authors named "Kenichi Yoshida"

289 Publications

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

Current Awareness and Status of Venous Ultrasonography in Kumamoto Prefecture - A Report of the Kumamoto Cardiovascular Echocardiography Standardization Project.

Circ Rep 2021 Aug 29;3(8):449-456. Epub 2021 Jun 29.

Department of Laboratory Medicine, Kumamoto University Hospital Kumamoto Japan.

There are few reports on the current awareness and status of venous ultrasonography, including the number of specialists who perform this procedure, in a specific regional area in Japan. This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. Of the 366 medical institutions providing cardiology services in Kumamoto Prefecture, 259 (101 general hospitals, 158 small clinics) responded to our questionnaire. In 2017, 21,773 venous ultrasound tests were performed, 21,101 (97%) of which were performed in hospitals and only 672 (3%) were performed in clinics. Both the number of institutions performing venous ultrasounds and the number of tests performed increased over time. Although 317 medical staff in Kumamoto Prefecture were performing transthoracic echocardiography (TTE) when the questionnaires were collected, only 210 performed venous ultrasounds. Although 91% (61/67) of medical institutions could perform TTE within 30 min, only 77% (53/69) performed venous ultrasounds within 30 min. The number of venous ultrasounds per population×100 was largest in the Kumamoto and Kamimashiki areas (1.67) and smallest in the Kamoto area (0.05). This is the first report to reveal the current awareness and status of venous ultrasonography in a specific region in Japan. There are several problems to be overcome, such as a lack of venous ultrasound specialists and the regional disparity in venous ultrasounds in Kumamoto Prefecture.
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http://dx.doi.org/10.1253/circrep.CR-21-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338438PMC
August 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

Droplet digital polymerase chain reaction assay for the detection of the minor clone of KIT D816V in paediatric acute myeloid leukaemia especially showing RUNX1-RUNX1T1 transcripts.

Br J Haematol 2021 Jul 13;194(2):414-422. Epub 2021 Jun 13.

Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1-RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)-AML patients. The 5 year event-free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%-69.4%] vs. 74.7% [95% CI, 63.0%-83.2%] P-value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%-NA vs. 89.7% [95% CI, 69.6%-96.8%] P-value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF-AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1-RUNX1T1-positive AML.
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http://dx.doi.org/10.1111/bjh.17569DOI Listing
July 2021

Quality Verification with a Cluster-Controlled Manufacturing System to Generate Monocyte-Derived Dendritic Cells.

Vaccines (Basel) 2021 May 20;9(5). Epub 2021 May 20.

Department of Regenerative Medicine, Kanazawa Medical University, Uchinada, Kahoku, Ishikawa 920-0293, Japan.

Dendritic cell (DC) vaccines for cancer immunotherapy have been actively developed to improve clinical efficacy. In our previous report, monocyte-derived DCs induced by interleukin (IL)-4 with a low-adherence dish (low-adherent IL-4-DCs: la-IL-4-DCs) improved the yield and viability, as well as relatively prolonged survival in vitro, compared to IL-4-DCs developed using an adherent culture protocol. However, la-IL-4-DCs exhibit remarkable cluster formation and display heterogeneous immature phenotypes. Therefore, cluster formation in la-IL-4-DCs needs to be optimized for the clinical development of DC vaccines. In this study, we examined the effects of cluster control in the generation of mature IL-4-DCs, using cell culture vessels and measuring spheroid formation, survival, cytokine secretion, and gene expression of IL-4-DCs. Mature IL-4-DCs in cell culture vessels (cluster-controlled IL-4-DCs: cc-IL-4-DCs) displayed increased levels of CD80, CD86, and CD40 compared with that of la-IL-4-DCs. cc-IL-4-DCs induced antigen-specific cytotoxic T lymphocytes (CTLs) with a human leukocyte antigen (HLA)-restricted melanoma antigen recognized by T cells 1 (MART-1) peptide. Additionally, cc-IL-4-DCs produced higher levels of IFN-γ, possessing the CTL induction. Furthermore, DNA microarrays revealed the upregulation of BCL2A1, a pro-survival gene. According to these findings, the cc-IL-4-DCs are useful for generating homogeneous and functional IL-4-DCs that would be expected to promote long-lasting effects in DC vaccines.
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http://dx.doi.org/10.3390/vaccines9050533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160655PMC
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

Lineage tracing of human development through somatic mutations.

Nature 2021 07 12;595(7865):85-90. Epub 2021 May 12.

Wellcome Trust Sanger Institute, Hinxton, UK.

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.
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http://dx.doi.org/10.1038/s41586-021-03548-6DOI Listing
July 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

Poor Myocardial Compaction in a Patient with Recessive MYL2 Myopathy.

Int Heart J 2021 Mar 17;62(2):445-447. Epub 2021 Mar 17.

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

Recessive mutations in the Myosin regulatory light chain 2 (MYL2) gene are the cause of an infantile-onset myopathy, associated with fatal myocardial disease of variable macromorphology. We here present the first Japanese family affected with recessive MYL2 myopathy. Affected siblings manifested typical features and the proband's autopsy findings were compatible with the diagnosis of noncompaction cardiomyopathy. The rapidly progressive clinical course of this recessive MYL2 cardiomyopathy highlights the crucial role of c-terminal tails in MYL2 protein in maintaining cardiac morphology and function.
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http://dx.doi.org/10.1536/ihj.20-639DOI Listing
March 2021

Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.

Haematologica 2021 Mar 18. Epub 2021 Mar 18.

Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan; Institute of Physiology and Medicine, Jobu University, Gunma.

RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) out of 328 patients: NF1 (n = 7, 2.1%), PTPN11 (n = 15, 4.6%), CBL (n = 6, 1.8%), NRAS (n = 44, 13.4%), KRAS (n = 12, 3.7%). Most of these alterations were mutually exclusive and were also mutually exclusive with other aberrations of signal transduction pathways such as FLT3-ITD (p = 0.001) and KIT mutation (p = 0.004). NF1 alterations were frequently detected in patients with complex karyotype (p = 0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (p = 0.007). At least four of seven patients with NF1 alterations had bi-allelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis [OS, p = 0.023; event-free survival (EFS), p = 0.037]. Patients with PTPN11 mutations more frequently received stem cell transplantation (p = 0.035) and showed poor EFS than patients without PTPN11 mutations (p = 0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
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http://dx.doi.org/10.3324/haematol.2020.269431DOI Listing
March 2021

Current Awareness and Status of Transthoracic Echocardiography in Kumamoto Prefecture - A Report of the Kumamoto Cardiovascular Echocardiography Standardization Project.

Circ Rep 2020 Apr 21;2(6):297-305. Epub 2020 Apr 21.

Department of Laboratory Medicine, Kumamoto University Hospital Kumamoto Japan.

There are few reports on current awareness and status of transthoracic echocardiography (TTE), including the actual performance rate according to echocardiographic guidelines, in a specific area or region. This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. There are 366 medical institutions advocating cardiology in Kumamoto Prefecture. Of these, 259 (101 hospitals and 158 clinics) returned questionnaires regarding TTE. In all, 150,570 TTEs were performed in 2017. Of these, 132,771 (88%) were performed in hospitals and 17,799 (12%) were performed in clinics. Physicians performed only 5% of TTEs, whereas sonographers performed 86%. Although the modified Simpson method was performed in 90% of hospitals, 3-dimensional echocardiography was performed in only 2% of hospitals. In addition, the left atrial volume index was not examined in approximately 60% of hospitals, and the mean E/E' ratio was not examined in 80% of hospitals. Multivariable logistic regression analysis revealed that having a Fellow of the Japan Society of Ultrasonic in Medicine was significantly and independently associated with guideline-oriented TTE (odds ratio 9.43; 95% confidence interval 1.22-72.71, P<0.05). The rate of echocardiographic measurements performed according to echocardiographic guidelines is exceptionally low in Kumamoto Prefecture. Sufficient dissemination of echocardiographic guidelines may be important in improving this rate.
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http://dx.doi.org/10.1253/circrep.CR-20-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925316PMC
April 2020

Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency.

Front Endocrinol (Lausanne) 2021 19;12:578802. Epub 2021 Feb 19.

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Objective: Heterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies.

Design And Methods: We analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies.

Results: Immunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high.

Conclusions: Patients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.
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http://dx.doi.org/10.3389/fendo.2021.578802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933588PMC
February 2021

Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency.

Blood 2021 04;137(15):2021-2032

Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center.

We have recently discovered Japanese children with a novel Fanconi anemia-like inherited bone marrow failure syndrome (IBMFS). This disorder is likely caused by the loss of a catabolic system directed toward endogenous formaldehyde due to biallelic variants in ADH5 combined with a heterozygous ALDH2*2 dominant-negative allele (rs671), which is associated with alcohol-induced Asian flushing. Phytohemagglutinin-stimulated lymphocytes from these patients displayed highly increased numbers of spontaneous sister chromatid exchanges (SCEs), reflecting homologous recombination repair of formaldehyde damage. Here, we report that, in contrast, patient-derived fibroblasts showed normal levels of SCEs, suggesting that different cell types or conditions generate various amounts of formaldehyde. To obtain insights about endogenous formaldehyde production and how defects in ADH5/ALDH2 affect human hematopoiesis, we constructed disease model cell lines, including induced pluripotent stem cells (iPSCs). We found that ADH5 is the primary defense against formaldehyde, and ALDH2 provides a backup. DNA repair capacity in the ADH5/ALDH2-deficient cell lines can be overwhelmed by exogenous low-dose formaldehyde, as indicated by higher levels of DNA damage than in FANCD2-deficient cells. Although ADH5/ALDH2-deficient cell lines were healthy and showed stable growth, disease model iPSCs displayed drastically defective cell expansion when stimulated into hematopoietic differentiation in vitro, displaying increased levels of DNA damage. The expansion defect was partially reversed by treatment with a new small molecule termed C1, which is an agonist of ALDH2, thus identifying a potential therapeutic strategy for the patients. We propose that hematopoiesis or lymphocyte blastogenesis may entail formaldehyde generation that necessitates elimination by ADH5/ALDH2 enzymes.
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http://dx.doi.org/10.1182/blood.2020009111DOI Listing
April 2021

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

Blood 2021 03;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

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism.

PLoS One 2021 19;16(1):e0245526. Epub 2021 Jan 19.

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

Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815088PMC
June 2021

Unbiased Detection of Driver Mutations in Extramammary Paget Disease.

Clin Cancer Res 2021 03 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

Novel COL4A1 mutations identified in infants with congenital hemolytic anemia in association with brain malformations.

Hum Genome Var 2020 Nov 27;7(1):42. Epub 2020 Nov 27.

Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University, Tokyo, Japan.

Genetic causes of undiagnosed hemolytic anemia in nineteen patients were analyzed by whole-exome sequencing, and novel COL4A1 variants were identified in four patients (21%). All patients were complicated with congenital malformations of the brain, such as porencephaly or schizencephaly. In these patients, hemolysis became less severe within 2 months after birth, and red cell transfusion was no longer required after 50 days, whereas chronic hemolysis continued.
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http://dx.doi.org/10.1038/s41439-020-00130-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695726PMC
November 2020

Acquisition of monosomy 7 and a RUNX1 mutation in Pearson syndrome.

Pediatr Blood Cancer 2021 02 16;68(2):e28799. Epub 2020 Nov 16.

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

Pearson syndrome (PS) is a very rare and often fatal multisystem disease caused by deletions in mitochondrial DNA that result in sideroblastic anemia, vacuolization of marrow precursors, and pancreatic dysfunction. Spontaneous recovery from anemia is often observed within several years of diagnosis. We present the case of a 4-month-old male diagnosed with PS who experienced prolonged severe pancytopenia preceding the emergence of monosomy 7. Whole-exome sequencing identified two somatic mutations, including RUNX1 p.S100F that was previously reported as associated with myeloid malignancies. The molecular defects associated with PS may have the potential to progress to advanced myelodysplastic syndrome .
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http://dx.doi.org/10.1002/pbc.28799DOI Listing
February 2021

Quantitative structure-property relationships for the calculation of the soil adsorption coefficient using machine learning algorithms with calculated chemical properties from open-source software.

Environ Res 2021 05 22;196:110363. Epub 2020 Oct 22.

Graduate School of Business Sciences, University of Tsukuba, 3-29-1 Otsuka, Bunkyo-ku, 112-0012, Tokyo, Japan.

The soil adsorption coefficient (K) is an environmental fate parameter that is essential for environmental risk assessment. However, obtaining K requires a significant amount of time and enormous expenditure. Thus, it is necessary to efficiently estimate K in the early stages of a chemical's development. In this study, a quantitative structure-property relationship (QSPR) model was developed using calculated physicochemical properties and molecular descriptors with the OPEn structure-activity/property Relationship App (OPERA) and Mordred software using the largest available K dataset. Specifically, we compared the accuracies of the model using the light gradient boosted machine (LightGBM), a gradient boosting decision tree (GBDT) algorithm, with those of previous models. The experimental results suggested the potential to develop a QSPR model that will produce highly accurate K values using molecular descriptors and physicochemical properties. Unlike previous studies, the use of a combination of LightGBM, OPERA and Mordred enables the prediction of K for many chemicals with high accuracy. In this study, OPERA was used to calculate the physicochemical properties, and Mordred was used to calculate molecular descriptors. The wide range of chemicals covered by OPERA and Mordred enables the analysis of a diverse range of chemical compounds. We also report a method to tune the LightBGM program. The use of fast-processing software, such as LightGBM, enables parameter tuning of a method required to obtain best performance. Our research represents one of the few studies in the field of environmental chemistry to use LightGBM. Using physicochemical properties as well as molecular descriptors, we could develop highly accurate K prediction models when compared to prior studies. In addition, our QSPR models may be useful for preliminary environmental risk assessment without incurring significant costs during the early chemical developmental stage.
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http://dx.doi.org/10.1016/j.envres.2020.110363DOI Listing
May 2021

Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.

Mol Cell 2020 12 3;80(6):996-1012.e9. Epub 2020 Nov 3.

Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan.

Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.
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http://dx.doi.org/10.1016/j.molcel.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758861PMC
December 2020

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

Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond-Blackfan anemia.

Bone Marrow Transplant 2021 05 18;56(5):1013-1020. Epub 2020 Sep 18.

Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond-Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.
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http://dx.doi.org/10.1038/s41409-020-01056-1DOI Listing
May 2021

Patients with pheochromocytoma exhibit low aldosterone renin ratio-preliminary reports.

BMC Endocr Disord 2020 Sep 11;20(1):140. Epub 2020 Sep 11.

Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Background: Plasma renin activity (PRA) is generally increased in patients with pheochromocytoma (PCC) due to low circulating plasma volume and activation of β-1 adrenergic receptor signaling. However, there has been no study on the aldosterone renin ratio (ARR) in patients with PCC. To elucidate the issue, this study aimed to determine the PRA, plasma aldosterone concentration (PAC), and ARR in patients with PCC and compare them with those in patients with subclinical Cushing's syndrome (SCS) and non-functioning adrenal adenoma (NFA).

Methods: In this retrospective single-center, cross-sectional study, 67 consecutive patients with adrenal tumors (PCC (n = 18), SCS (n = 18), and NFA (n = 31)) diagnosed at Kobe University Hospital between 2008 and 2014 were enrolled.

Results: PRA was significantly higher in patients with PCC than in those with SCS and NFA (2.1 (1.3 ~ 2.8) vs. 0.7 (0.5 ~ 1.8) and 0.9 (0.6 ~ 1.4) ng/mL/h; p = 0.018 and p = 0.025). Although PACs were comparable among the three groups, ARR was significantly lower in patients with PCC than in those with SCS and NFA (70.5 (45.5 ~ 79.5) vs. 156.0 (92.9 ~ 194.5) and 114.9 (90.1 ~ 153.4); p = 0.001 and p < 0.001). Receiver operating characteristic curve analysis demonstrated that, in differentiating PCC from NFA, PRA > 1.55 ng/mL/h showed a sensitivity of 70.0% and specificity of 80.6%. Interestingly, ARR < 95.4 showed a sensitivity of 83.3% and specificity of 86.7%, which were higher than those in PRA.

Conclusions: ARR decreased in patients with PCC, which was a more sensitive marker than PRA. Further study is necessary to understand the usefulness of this convenient marker in the detection of PCC.

Trial Registration: This study was not registered because of the retrospective analysis.
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http://dx.doi.org/10.1186/s12902-020-00620-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488748PMC
September 2020
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