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1.
Nat Med ; 27(10): 1806-1817, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34621053

RESUMO

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

3.
Rinsho Ketsueki ; 62(8): 1029-1037, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497189

RESUMO

The development of gene analysis in cancer is remarkable, and understanding of molecular pathology has been elucidated. Somatic mutations, that is, genetic analysis in cancer cells, have contributed to the accurate diagnosis of tumors, prognostic prediction, and detection of therapeutic targets. In contrast, germline mutations have been identified as the cause of hereditary diseases. In the past, symptom diagnosis was the main focus for hereditary diseases. However, genetic information has greatly contributed to its definitive diagnosis. For hematopoietic malignancies, the 2016 revision of the World Health Organization classification newly proposed a section on myeloid neoplasms with germline predisposition. Genetic predispositions characterized by the development of lymphoid neoplasms and solid tumors have also been reported. Since 2016, new findings such as SAMD9/9L mutation have been discovered. This chapter outlines the typical genetic predisposition to myelodysplastic syndrome/leukemia.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética
6.
Pathol Int ; 71(5): 348-354, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713516

RESUMO

A 5-year-old girl presented with headache and vomiting. Head computed tomography and magnetic resonance imaging showed a right frontal lobe tumor with marked calcification. The patient underwent resection surgery with suspicion of anaplastic ependymoma, and the tumor was gross totally removed. Pathological examination revealed areas of dense tumor cells with a high nucleocytoplasmic ratio and myxoid areas consisting of tumor cells with a round-shaped nucleus and eosinophilic cytoplasm. Perivascular pseudorosette, necrosis, circumscribed growth, and microcalcification were also observed. Immunohistochemistry demonstrated negative staining for glial fibrillary protein and epithelial membrane antigen. Diagnosis of a high-grade neuroepithelial tumor (HGNET) with BCL6 corepressor (BCOR) alteration was made based on pathological findings and internal tandem duplication in the exon 15 of BCOR. Although calcification on radiological and pathological examination is not typical, it would be essential to recognize that calcification could appear in HGNET-BCOR.

7.
N Engl J Med ; 384(1): 42-50, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33406329

RESUMO

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).


Assuntos
Adenocarcinoma Mucinoso/etiologia , Carcinoma Neuroendócrino/etiologia , Neoplasias Pulmonares/etiologia , Complicações Neoplásicas na Gravidez , Neoplasias do Colo do Útero , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/genética , Adulto , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/genética , Carcinoma de Células Escamosas/patologia , Criança , Evolução Fatal , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mães , Gravidez , Vagina , Sequenciamento Completo do Exoma
8.
Int J Hematol ; 113(2): 297-301, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32979171

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a severe complication after allogeneic hematopoietic cell transplantation (HCT) and can cause graft failure or multi-organ failure. Here, we report two children with refractory HCT-associated HLH treated with ruxolitinib. In the first patient, ruxolitinib resolved fever, cytopenia and hyperferritinemia. In another patient, although severe hepatic failure, which developed and worsened before the administration of ruxolitinib, was irreversible, rapid improvement in fever, leukopenia and hyperferritinemia was observed. Of note, multiplex cytokine profiling showed amelioration of cytokine storm in both patients. Ruxolitinib may be an encouraging option for HCT-associated HLH.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Pirazóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Transplante Homólogo , Resultado do Tratamento
9.
Oncology ; 99(1): 23-31, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32906115

RESUMO

OBJECTIVE: Most types of intracranial germ cell tumors (IGCTs) are sensitive to chemoradiation. However, biopsy specimens are usually small and thus cannot be used for obtaining an accurate pathological diagnosis. Recently, the cerebrospinal fluid (CSF) placental alkaline phosphatase (PLAP) value has been considered a new biomarker of IGCTs. The present study aimed to evaluate the discriminatory characteristics of the CSF-PLAP value upon diagnosis and at the time of recurrence in patients with IGCTs. METHODS: Between 2015 and 2019, this study included 37 patients with tumors located in the intraventricular and/or periventricular region. The CSF-PLAP level was assessed before the patients received any treatment. The PLAP level was evaluated during and after first-line chemoradiotherapy in 7 patients with IGCTs. The CSF-PLAP values were compared according to histological diagnosis, and the correlation between these values and radiographical features was assessed. The CSF-PLAP values of 6 patients with IGCTs with suspected recurrence were evaluated based on neuroimaging findings. RESULTS: The CSF-PLAP values were significantly higher in patients with IGCTs than in those with other types of brain tumor (n = 19 vs. 18; median: 359.0 vs. <8.0 pg/mL). The specificity and sensitivity were 88 and 95%, respectively, with a cutoff value of 8.0 pg/mL. In patients with IGCT, the CSF-PLAP value was higher in patients with germinoma than in those with nongerminomatous germ cell tumors (n = 12 vs. 7; median: 415.0 vs. 359.0 pg/mL). Regarding the time course, the CSF-PLAP value decreased to below the detection limit after the reception of first-line chemoradiotherapy in all 7 patients. A significant correlation was observed between the initial CSF-PLAP value and the tumor reduction volume after receiving first-line chemoradiotherapy (p < 0.0003, R2 = 0.6165, logY = 1.202logX - 1.727). Among the patients with suspected IGCT recurrence (n = 6), the CSF-PLAP value was high in patients with recurrence (n = 3; median: 259.0 pg/mL), and that in patients (n = 3) without recurrence was below the lower detection limit. CONCLUSIONS: The CSF-PLAP level is a useful biomarker during the initial diagnosis of IGCTs and at the time of recurrence. It may be associated with the volume of germinomatous components of tumors.


Assuntos
Fosfatase Alcalina/líquido cefalorraquidiano , Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Encefálicas/líquido cefalorraquidiano , Isoenzimas/líquido cefalorraquidiano , Neoplasias Embrionárias de Células Germinativas/líquido cefalorraquidiano , Adolescente , Adulto , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Proteínas Ligadas por GPI/líquido cefalorraquidiano , Germinoma/líquido cefalorraquidiano , Germinoma/patologia , Humanos , Masculino , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Recidiva Local de Neoplasia/patologia , Neoplasias Embrionárias de Células Germinativas/enzimologia , Neoplasias Embrionárias de Células Germinativas/patologia , Adulto Jovem
10.
Pediatr Blood Cancer ; 68(2): e28799, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33200495

RESUMO

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 .


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Proteínas de Membrana/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Doenças Musculares/genética , Doenças Musculares/terapia , Proteínas do Tecido Nervoso/genética , Transfusão de Sangue , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , DNA Mitocondrial/genética , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Pancitopenia/genética , Pancitopenia/patologia , Sequenciamento Completo do Exoma
11.
Cancer Sci ; 111(9): 3367-3378, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619037

RESUMO

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).


Assuntos
Biomarcadores Tumorais , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
12.
Leukemia ; 34(10): 2673-2687, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32555368

RESUMO

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.


Assuntos
Deficiência de GATA2/genética , Fator de Transcrição GATA2/deficiência , Fator de Transcrição GATA2/genética , RNA/genética , Mutação Silenciosa/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Síndromes Mielodisplásicas/genética , Fenótipo , Adulto Jovem
14.
Oncol Lett ; 17(3): 3323-3329, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30867766

RESUMO

Recent genome-wide analysis of neuroblastoma (NBL) revealed amplification and heterozygous mutation of anaplastic lymphoma kinase (ALK) are responsible for oncogenicity, frequently observed during relapses. A 3-year-old girl with relapsed high-risk NBL had a heterozygous ALK F1245L mutation at diagnosis, which became homozygous due to uniparental disomy (UPD) of the entire chromosome 2, confirmed by single nucleotide polymorphism array and variant allele frequency of this mutation. The ALK inhibitor, crizotinib, failed to control the tumor and the patient died of the disease. Further genomic analysis using targeted capture sequencing for 381 genes related to pediatric cancers identified more alterations acquired at relapse, such as TSC complex subunit 2 and protein tyrosine phosphatase receptor type D. In addition to these several acquired mutations, this extremely rare duplication of ALK mutation might explain the aggressive clinical course after relapse, because acquired UPD, resulting in the duplication of an oncogenic mutation, has been reported for various neoplasms. Although a clinical benefit of ALK inhibitors in patients with NBL has not been confirmed yet, a treatment based on the ALK mutation status will be promising in future using more potent next-generation ALK inhibitors.

16.
Haematologica ; 104(1): 128-137, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171027

RESUMO

Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic µ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Translocação Genética , Adolescente , Criança , Intervalo Livre de Doença , Feminino , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Taxa de Sobrevida
17.
Rinsho Ketsueki ; 59(11): 2468-2474, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30531145

RESUMO

TP53 is a tumor-suppressor gene, and it is the most commonly mutated somatic gene in human cancer. Germline TP53 mutations correlate with a hereditary predisposition to cancer. Comprehensive genetic analysis revealed the role of germline and somatic TP53 gene mutations in hematological malignancies. TP53 mutations affect the prognosis and therapeutic decision-making. Hence, genetic screening and tumor surveillance, including family members, should be performed when a germline TP53 mutation is detected in a patient.


Assuntos
Neoplasias Hematológicas , Síndrome de Li-Fraumeni , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença , Humanos , Mutação
18.
Rinsho Ketsueki ; 59(4): 389-394, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29743397

RESUMO

An eight-year-old girl with myelodysplastic syndrome (refractory cytopenia) received a bone marrow transplant (BMT) from an unrelated donor because of immunosuppressive therapy failure. Following administration of foscarnet for cytomegalovirus reactivation at day40 post-BMT, serum creatinine increased, and proteinuria, hematuria, and hypertension gradually exacerbated and became prolonged. However, neither schistocytosis nor other organ damage was evident. At six months post-BMT, renal biopsy revealed diffuse glomerular damage with glomerular lobulation, a double contour of the glomerular basement membrane, erythrocyte congestion and thrombi in the glomerular endocapillaries, and mesangiolysis, confirming the diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA). We initiated strict controls regarding fluid balance, salt intake, and blood pressure. The patient's renal function improved 10 months post-BMT. TA-TMA often presents as non-specific symptoms, making diagnosis difficult. In cases of post-transplant renal damage, TA-TMA should be differentiated regardless of whether specific symptoms such as hemolytic anemia and other organ failure are evident, and a renal biopsy should, therefore, be considered.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Nefropatias/diagnóstico , Microangiopatias Trombóticas/diagnóstico , Biópsia , Criança , Feminino , Humanos , Rim/patologia
20.
Rinsho Ketsueki ; 58(10): 1878-1883, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28978828

RESUMO

The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. The study of cancer genomes has identified inherited genetic drivers that predispose cancer cells to clonal evolution. The revisions in the categories of myeloid neoplasms and acute leukemia were published as a monograph in 2016. We described familial hematological malignancies using the 2016 edition of the WHO classification.


Assuntos
Neoplasias Hematológicas , Cromossomos Humanos , Neoplasias Hematológicas/genética , Humanos
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