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1.
Nat Commun ; 12(1): 5183, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465776

RESUMO

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.


Assuntos
Linfoma Plasmablástico/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Amplificação de Genes , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/mortalidade , Linfoma Plasmablástico/terapia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Translocação Genética , Sequenciamento Completo do Exoma , Adulto Jovem
2.
Rinsho Ketsueki ; 62(8): 1308-1318, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497221

RESUMO

Leukemias diagnosed in <1-year-old infants generally have an aggressive clinical nature and unique biological characteristics. Acute lymphoblastic leukemia (ALL) in infants is still intractable and difficult to treat as compared with other pediatric ALLs, for which considerable progress in treatment outcomes has been recently achieved. Infant leukemia cells frequently carry chromosome translocations involving the 11q23 locus, resulting in the rearrangement and fusion of the KMT2A (MLL) gene. Among several KMT2A fusion genes, KMT2A-AFF1 (MLL-AF4) fusion is characteristically observed in neonatal and infant ALL, representing a hallmark of poor prognosis. The cytogenetic/molecular abnormalities t (1;22)(p13.3;q13.1)/RBM15-MKL1 and t (8;16)(p11.2;p13.3)/KAT6A-CREBBP (MOZ-CBP) are also well-known in acute myeloblastic leukemia in this population. Although many neonatal leukemias occurring within the first 28 days of birth are refractory, spontaneous remissions are occasionally observed, especially in the case of t (8;16). Therefore, international collaborative studies are necessary to improve understanding and facilitate the development of better treatment for this rare disease. Thus, this study summarizes the recently reported clinical, cytogenetic, and molecular biology aspects of neonatal and infant leukemias.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Aberrações Cromossômicas , Humanos , Lactente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Translocação Genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 845-848, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487527

RESUMO

OBJECTIVE: To assess the application value of mapping allele with resolved carrier status (MaReCs) technique for preimplantation genetic testing (PGT). METHODS: The characteristics of MaReCs for PGT and outcome of patients were retrospectively analyzed. RESULTS: Compared with those who could not use the technique, carriers who have used the MaReCs technique were younger, had significantly higher level of anti-Mullerian hormone, more antral follicles, occytes, mature occytes, biopsied embryos and euploid embryos, and lower risks for de novo chromosomal abnormality (P<0.05). It was necessary for couples with fewer oocytes, mature oocytes and balstocyst to preserve discarded embryos to facilitate the test. Carriers who have used the MaReCs technique had higher clinical pregnancy rate and abortion rate compared with those undergoing routine PGT, albeit no significant difference was found between the two groups (P> 0.05). Carriers undergoing MaReCs test could preferentially select embryos with normal chromosome structures for the transfer. CONCLUSION: Application of MaReCs has a prerequisite for having a minimum number of occytes and biopsied embryos and using discarded embryos sometimes. MaReCs is efficient for the detection of carrier status of embryos and attaining higher rate of pregnancy and live birth, which can significantly improve the outcome for couples carrying chromosomal translocations.


Assuntos
Diagnóstico Pré-Implantação , Translocação Genética , Alelos , Aneuploidia , Blastocisto , Feminino , Fertilização In Vitro , Testes Genéticos , Humanos , Gravidez , Estudos Retrospectivos
4.
Hematology ; 26(1): 691-696, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34493159

RESUMO

Objective: The 8p11 myeloproliferative syndrome [EMS] is a rare myeloproliferative disorder which usually develops rapidly with chromosomal translocation of the fibroblast growth factor receptor 1 gene. The gene has 15 fusion partners, including the breakpoint cluster region (BCR) gene on chromosome 22. Of all the tests available, chromosome karyotype determination is the most important for the diagnosis of EMS. Here, we describe one case of a patient characterized by marked increase of white blood cells and thrombocytopenia and diagnosed as EMS with t(8;22)(p11;q11) by chromosome karyotype.Methods: 28-year-old man was referred to our hospital. He had a onemonth history of intermittent coughing and a small amount of expectoration after catching a cold. As an outpatient, his complete blood count showed: WBC was 130.04 × 109/L with 80.20% granulocytes.Hematologic investigations, bone marrow analysis and genomic DNA sequencing studies were performed.Results: Despite additional chromosomal abnormalities,the patient progressed rapidly with a B blast cell clone in one month. After diagnosis inthree months, the patient underwent the haplo-identical BMT of his brother, followed up for three years, and had a high rate of survival.Conclusions: Our report provides a definite conceptual framework for a better understanding of the characteristics of The 8p11 myeloproliferative syndrome [EMS].


Assuntos
Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 8/genética , Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-bcr/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Translocação Genética , Adulto , Aloenxertos , Humanos , Masculino , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Síndrome
5.
Rinsho Ketsueki ; 62(7): 809-819, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34349066

RESUMO

Acute lymphoblastic leukemia (ALL) in infants remains an intractable and difficult-to-treat leukemia as compared to other pediatric ALLs, for which considerable progress has been achieved in terms of treatment outcomes in recent years. The leukemic cells in infants with ALL frequently carry chromosome translocations involving 11q23, resulting in the rearrangement and fusion of the MLL (KMT2A) gene. Among many MLL fusion genes, MLL-AF4 (KMT2A-AFF1) fusion is characteristically observed in infants with ALL, representing a hallmark of poor prognosis. In MLL-AF4-positive infants with ALL, first leukemic cells with MLL-AF4 were generated in utero. Analysis of several murine and human leukemia models revealed that the target cells for tumorigenesis by MLL-AF4 were not the hematopoietic progenitor cells of the bone marrow, but the early hematopoietic progenitor cells present in the fetal liver during the embryonic period and possibly the undifferentiated cells prior to the commitment to hematopoietic cells in the fetus. Elucidation of the leukemogenic process of infant ALL with MLL-AF4 may lead to early, pre-symptomatic diagnosis of leukemia, resulting in the improvement of prognosis and prevention of the onset of ALL in infants.


Assuntos
Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Medula Óssea , Criança , Células-Tronco Hematopoéticas , Humanos , Lactente , Camundongos , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Translocação Genética
6.
Nucleic Acids Res ; 49(15): 8732-8742, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34365511

RESUMO

CRISPR-Cas9 generates double-stranded DNA breaks (DSBs) to activate cellular DNA repair pathways for genome editing. The repair of DSBs leads to small insertions or deletions (indels) and other complex byproducts, including large deletions and chromosomal translocations. Indels are well understood to disrupt target genes, while the other deleterious byproducts remain elusive. We developed a new in silico analysis pipeline for the previously described primer-extension-mediated sequencing assay to comprehensively characterize CRISPR-Cas9-induced DSB repair outcomes in human or mouse cells. We identified tremendous deleterious DSB repair byproducts of CRISPR-Cas9 editing, including large deletions, vector integrations, and chromosomal translocations. We further elucidated the important roles of microhomology, chromosomal interaction, recurrent DSBs, and DSB repair pathways in the generation of these byproducts. Our findings provide an extra dimension for genome editing safety besides off-targets. And caution should be exercised to avoid not only off-target damages but also deleterious DSB repair byproducts during genome editing.


Assuntos
Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Reparo do DNA , Edição de Genes , Animais , Células Cultivadas , Simulação por Computador , Humanos , Camundongos , Plasmídeos/genética , Deleção de Sequência , Translocação Genética
7.
Oncol. (Guayaquil) ; 31(2): 141-154, 31 de agosto 2021.
Artigo em Espanhol | LILACS | ID: biblio-1284452

RESUMO

Introducción: La leucemia linfoblástica aguda (LLA) es la neoplasia maligna de mayor frecuencia en la infancia; advertir sus alteraciones moleculares y citogenéticas permite establecer el riesgo, el pronóstico asociado y además plantear esquemas terapéuticos apropiados; el objetivo de este estudio es conocer la prevalencia de estas alteraciones en nuestra población. Metodología: Estudio de tipo retrospectivo y transversal, basado en los registros de las alteraciones moleculares y citogenéticas de los pacientes pediátricos diagnosticados con leucemia linfoblástica aguda durante el periodo comprendido entre enero 2014 a diciembre de 2018, en el Hospital del Instituto Oncológico Nacional "Dr. Juan Tanca Marengo". Resultados: Se incluyeron 338 pacientes, de los cuales el principal grupo etario lo constituyo el de 0 a 4 años; el inmunofenotipo más observado fue el B-común. En el 24.56% de los casos se detectó altercaciones estructurales, principalmente por estudios de biología molecular; siendo la más común la translocación t(12;21). Se obtuvieron resultados por citogenética en 167 pacientes, en cuales la principal alteración numérica correspondió a la hiperdiploidía de entre 47 a 51 cromosomas. Conclusión: Los avances en la caracterización molecular y citogenética de la LLA, permiten mejorar la estratificación de su riesgo; y establecer estrategias terapéuticas que permitan una mejoría en la sobrevida.


Introduction: Acute lymphoblastic leukemia (ALL) is the most frequent malignant neoplasm in childhood; Noting its molecular and cytogenetic alterations allows to establish the risk, the associat-ed prognosis and also to propose appropriate therapeutic schemes; The objective of this study is to know the prevalence of these alterations in our population. Methods: Retrospective and cross-sectional study, based on the records of molecular and cytogenetic alterations of pediatric patients diagnosed with acute lymphoblastic leukemia during the period from January 2014 to December 2018, at the National Oncological Institute Hospital "Dr. Juan Tanca Marengo". Results: 338 patients were included, of which the main age group was made up of 0 to 4 years; the most observed immunophenotype was B-common. In 24.56% of the cases, structural alterations were detected, mainly by molecular biology studies; the most common being the t (12; 21) translocation. Cytogenetics results were obtained in 167 patients, in which the main numerical alteration corresponded to hyperdiploidy of between 47 and 51 chromosomes. Conclusions: Advances in the molecular and cytogenetic characterization of ALL make it possible to improve the stratification of its risk; and establish therapeutic strategies that achieve an improvement in survival.


Introdução: A leucemia linfoblástica aguda (LLA) é a neoplasia maligna mais comum na infância; Observar suas alterações moleculares e citogenéticas permite estabelecer o risco, o prognóstico associado e também propor esquemas terapêuticos adequados; O objetivo deste estudo é conhecer a prevalência dessas alterações em nossa população. Metodologia: Estudo retrospectivo e transversal, baseado nos registros de alterações moleculares e citogenéticas de pacientes pediátricos com diagnóstico de leucemia linfoblástica aguda no período de janeiro de 2014 a dezembro de 2018, no Hospital del Instituto Oncológico Nacional "Dr. Juan Tanca Marengo ". Resultados: Foram incluídos 338 pacientes, cuja faixa etária principal era de 0 a 4 anos; o imunofenótipo mais observado foi B-comum. Em 24,56% dos casos, foram detectadas alterações estruturais, principalmente por estudos de biologia molecular; o mais comum é a translocação t (12; 21). Os resultados citogenéticos foram obtidos em 167 pacientes, nos quais a principal alteração numérica correspondeu à hiperdiploidia entre 47 e 51 cromossomos. Conclusão: Os avanços na caracterização molecular e citogenética da LLA permitiram melhorar a estratificação de risco; e estabelecer estratégias terapêuticas que permitam uma melhora na sobrevida.


Assuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Leucemia Aguda Bifenotípica , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Translocação Genética , Criança , Citogenética
8.
BMC Res Notes ; 14(1): 259, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34225806

RESUMO

OBJECTIVE: Pediatric acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer among children. This study was conducted to describe and correlate the clinical characteristics and outcomes of treatment of patients with pediatric ALL in the main referral hospital in Palestine. RESULTS: Complete data of 69 patients were included in this analysis. The majority (79.7%) of the patients had B-ALL phenotype. After induction chemotherapy, remission was experienced by the vast majority of the patients and 5 (7.2%) experienced relapses. Cytogenetics for patients with B-ALL phenotype indicated that 10 (18.2%) patients had t(12, 21) translocation, 5 (9.1%) had hyperdiploidy, 4 (7.3%) had t(1, 19) translocation, and 2 (3.6%) had t(9, 22) translocation. The initial white blood cells (p value < 0.001), absolute neutrophils (p value = 0.011), and hemoglobin (p value < 0.001) were significantly lower in patients with B-cell ALL. Platelet counts were significantly lower (p value = 0.012) in patients with splenomegaly and those with bleeding symptoms (p value = 0.008). Presence of palmar pollar was positively associated (p value = 0.035) with T-cell ALL. Presence of hepatomegaly was positively associated (p value < 0.001) with splenomegaly.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Quimioterapia de Indução , Contagem de Leucócitos , Neutrófilos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Indução de Remissão , Translocação Genética
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202474

RESUMO

Salivary gland tumors are a rare tumor entity within malignant tumors of all tissues. The most common are malignant mucoepidermoid carcinoma, adenoid cystic carcinoma, and acinic cell carcinoma. Pleomorphic adenoma is the most recurrent form of benign salivary gland tumor. Due to their low incidence rates and complex histological patterns, they are difficult to diagnose accurately. Malignant tumors of the salivary glands are challenging in terms of differentiation because of their variability in histochemistry and translocations. Therefore, the primary goal of the study was to review the current literature to identify the recent developments in histochemical diagnostics and translocations for differentiating salivary gland tumors.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Testes Genéticos , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Translocação Genética , Estudos de Associação Genética , Testes Genéticos/métodos , Testes Genéticos/normas , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/normas , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/terapia
10.
Cancer Sci ; 112(9): 3645-3654, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288263

RESUMO

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Translocação Genética/genética , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tretinoína/farmacologia
11.
Nat Commun ; 12(1): 4130, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226546

RESUMO

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.


Assuntos
Doença Aguda , Leucemia Mieloide Aguda/genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Translocação Genética/genética , Animais , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Cromatina , Células HEK293 , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Metilação , Camundongos , Modelos Moleculares , Proteínas Monoméricas de Montagem de Clatrina/genética , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Nucleossomos , Conformação Proteica
12.
BMJ Case Rep ; 14(6)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172479

RESUMO

Xp11.2 translocation renal cell carcinoma (TRCC) is a rare and aggressive variant of renal cell carcinoma (RCC) when presenting in adults. We report a case of a man in his early 40s who was diagnosed with stage III Xp11.2 TRCC and underwent radical nephrectomy. Seven months following the surgery, an adrenal nodule and bilateral pulmonary nodules were discovered. He underwent cryoablation of the adrenal nodule and systemic treatment with daily pazopanib. He displayed stable disease for approximately 6 years. Following this period, multiple hospitalisations interrupted daily pazopanib therapy resulting in progression of disease. His regimen was then changed to ipilimumab and nivolumab, followed by current daily therapy with axitinib. The patient now shows stable disease in his 10th year after diagnosis. This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation to supplement the guidelines regarding the use of targeted therapy for TRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Adulto , Carcinoma de Células Renais/genética , Cromossomos Humanos X , Humanos , Indazóis , Neoplasias Renais/genética , Masculino , Pirimidinas , Sulfonamidas , Translocação Genética
13.
Nat Commun ; 12(1): 3708, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140506

RESUMO

3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.


Assuntos
Cromossomos/metabolismo , Proteínas de Homeodomínio/genética , Leucemia-Linfoma de Células T do Adulto/genética , Conformação Molecular , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Linfócitos T/metabolismo , Translocação Genética , Acetilação , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Criança , Sequenciamento de Cromatina por Imunoprecipitação , Cromossomos/genética , Progressão da Doença , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/genética , Regulação Leucêmica da Expressão Gênica/imunologia , Ontologia Genética , Hematopoese/genética , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Imunofenotipagem , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/mortalidade , Leucemia-Linfoma de Células T do Adulto/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Linfócitos T/patologia , Adulto Jovem
14.
Hum Genet ; 140(8): 1241-1252, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34059954

RESUMO

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas with poor prognosis, developing either sporadically or in persons with neurofibromatosis type 1 (NF1). Loss of CDKN2A/B is an important early event in MPNST progression. However, many reported MPNSTs exhibit partial or no inactivation of CDKN2A/B, raising the question of whether there is more than one molecular path for MPNST initiation. We present here a comprehensive genomic analysis of MPNST cell lines and tumors to explore in depth the status of CDKN2A. After accounting for CDKN2A deletions and point mutations, we uncovered a previously unnoticed high frequency of chromosomal translocations involving CDKN2A in both MPNST cell lines and primary tumors. Most identified translocation breakpoints were validated by PCR amplification and Sanger sequencing. Many breakpoints clustered in an intronic 500 bp hotspot region adjacent to CDKN2A exon 2. We demonstrate the bi-allelic inactivation of CDKN2A in all tumors (n = 15) and cell lines (n = 8) analyzed, supporting a single molecular path for MPNST initiation in both sporadic and NF1-related MPNSTs. This general CDKN2A inactivation in MPNSTs has implications for MPNST diagnostics and treatment. Our findings might be relevant for other tumor types with high frequencies of CDKN2A inactivation.


Assuntos
Carcinogênese/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neurofibromatose 1/genética , Neurofibrossarcoma/genética , Polimorfismo de Nucleotídeo Único , Sarcoma/genética , Translocação Genética , Sequência de Bases , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Cromossomos Humanos Par 9 , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Éxons , Genoma Humano , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/metabolismo , Neurofibromatose 1/patologia , Neurofibrossarcoma/etiologia , Neurofibrossarcoma/metabolismo , Neurofibrossarcoma/patologia , Sarcoma/etiologia , Sarcoma/metabolismo , Sarcoma/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Sequenciamento Completo do Genoma
15.
Virchows Arch ; 479(2): 247-255, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34173019

RESUMO

With this external quality assessment (EQA) scheme, we aim to investigate the diagnostic performance of the currently available methods for the detection of ALK alterations in non-small cell lung cancer on a national scale, namely, in situ hybridization (ISH), immunohistochemistry (IHC), and RNA/DNA sequencing (NGS). The EQA scheme cohort consisted of ten specimens, including four ALK positive and six ALK negative samples, which were thoroughly pretested using IHC, ISH, and RNA/DNA NGS. Unstained tumor sections were provided to the 57 participants, and the results were retrieved via an online questionnaire. ISH was used by 29, IHC by 38, and RNA/DNA sequencing by 19 participants. Twenty-eight institutions (97%) passed the ring trial using ISH, 33 (87%) by using IHC, and 18 (95%) by using NGS. The highest sensitivity and interrater agreement (Fleiss ' kappa) was observed for RNA/DNA sequencing (99%, 0.975), followed by ISH (94%, 0.898) and IHC (92%, 0.888). However, the proportion of samples that were not evaluable due to bad tissue quality was also higher for RNA/DNA sequencing (4%) compared with ISH (0.7%) and IHC (0.5%). While all three methods produced reliable results between the different institutions, the highest sensitivity and concordance were observed for RNA/DNA sequencing. These findings encourage the broad implementation of this method in routine diagnostic, although the application might be limited by technical capacity, economical restrictions, and tissue quality of formalin-fixed samples.


Assuntos
Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Imuno-Histoquímica , Hibridização In Situ , Neoplasias Pulmonares/genética , Análise de Sequência de DNA , Análise de Sequência de RNA , Translocação Genética , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Alemanha , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ensaio de Proficiência Laboratorial , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
16.
Int J Biol Macromol ; 185: 403-411, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34166699

RESUMO

Gene rearrangements have been found in several mitochondrial genomes of Mantodea, located in the gene blocks CR-I-Q-M-ND2, COX1-K-D-ATP8 and ND3-A-R-N-S-E-F-ND5. We have sequenced one mitogenome of Amelidae (Yersinia mexicana) and six mitogenomes of Mantidae to discuss the mitochondrial gene rearrangement and the phylogenetic relationship within Mantidae. These mitogenomes showed rearrangements of tRNA genes except for Asiadodis yunnanensis and Hierodula zhangi. These novel gene rearrangements of Mantidae were primarily concentrated in the region of CR-I-Q-M-ND2, including gene translocation, duplication and pseudogenization. For the occurrences of these rearrangements, the tandem duplication-random loss (TDRL) model and slipped-strand mispairing model were suitable to explain. Large non-coding regions (LNCRs) located in the region of CR-I-Q-M-ND2 were detected in most Mantidae species, whereas some LNCRs had high similarity to the control region (CR). Both BI and ML phylogenetic analyses supported the monophyly of Mantidae and the paraphyly of Mantinae. The phylogenetic results with the gene order and the location of NCRs acted as forceful evidence that specific gene rearrangements and special LNCRs may be synapomorphies for several groups of mantises.


Assuntos
Rearranjo Gênico , Mantódeos/genética , Mitocôndrias/genética , RNA de Transferência/genética , Animais , Evolução Molecular , Duplicação Gênica , Ordem dos Genes , Genoma Mitocondrial , Conformação de Ácido Nucleico , Filogenia , Pseudogenes , RNA de Plantas/genética , RNA de Transferência/química , Análise de Sequência de DNA , Translocação Genética
17.
Mol Cell ; 81(12): 2504-2506, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34143968

RESUMO

A spectrum of cancers arises from chromosomal translocations that fuse receptor tyrosine kinase domains to oligomerization domains from unrelated proteins. Tulpule et al. (2021) demonstrate that fusion proteins with the ability to assemble higher-order cytoplasmic protein granules can activate RAS signaling in a lipid membrane-independent manner.


Assuntos
Receptores Proteína Tirosina Quinases , Transdução de Sinais , Carcinogênese , Humanos , Oncogenes/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Translocação Genética
18.
Clin Lab ; 67(6)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34107633

RESUMO

BACKGROUND: Balanced translocation of chromosomes has a negative impact on male fertility, which can easily cause clinical manifestations such as oligospermia and asthenospermia. It is necessary to conduct cytogenetic examination on men of childbearing age to guide them in their fertility. METHODS: We report a case of balanced translocation: 46, XY, t(9;22) (q22;q13) accompanied with oligospermia and asthenospermia. The lymphocytes in peripheral blood were cultured to examine the patient's karyotype. RESULTS: The karyotypes of the patient and the patient's wife were detected and identified as 46, XY, t(9;22) (9pter→9q22::22q13→22qter;22pter→22q13::9q22→9qter) and 46, XX, respectively. The origin of the chromosome translocation was unknown because the patient's parents did not undergo cytogenetic tests. CONCLUSIONS: For patients with oligospermia and asthenospermia, cytogenetic examination should be carried out to obtain a healthy fetus. Prenatal diagnosis should be strictly performed to prevent the birth of children with chromosomal diseases if one partner of the couple is a carrier with abnormal chromosome structure.


Assuntos
Transtornos Cromossômicos , Oligospermia , Criança , Aberrações Cromossômicas , Feminino , Humanos , Cariotipagem , Masculino , Oligospermia/diagnóstico , Oligospermia/genética , Gravidez , Translocação Genética
19.
Zhonghua Bing Li Xue Za Zhi ; 50(6): 604-608, 2021 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-34078047

RESUMO

Objective: To investigate the clinicopathological features, molecular genetics, treatment and prognosis of Burkitt-like lymphoma with 11q aberration (BLL-11q). Methods: Six cases of BLL-11q diagnosed at the First Affiliated Hospital of Zhengzhou University, from January 2016 to January 2020 were reviewed and analyzed using hematoxylin-eosin staining, immunohistochemistry, EBER in situ hybridization and fluorescence in situ hybridization. Clinical information including follow-up data was collected and analyzed. Results: The median age of the six immunocompetent patients was 29 years (range 20-38 years) and the male to female ratio was 5∶1. All patients had nodal disease in the head and neck region. Five patients had Ann Arbor stage Ⅰ-Ⅱ disease, while one patient had stage Ⅳ disease. Lymph nodes showed partial or total architectural effacement by a diffuse proliferation of monomorphic lymphocytes. Four cases were morphologically similar to Burkitt lymphoma, and two cases were unclassified with histological features between Burkitt lymphoma and diffuse large B-cell lymphoma. Mitotic figures, apoptosis and necrosis were conspicuous. Five cases exhibited the"starry sky"pattern. CD20, CD10 and bcl-6 were diffusely and strongly positive. The Ki-67 index was more than 95%. The follicular-dendritic-cell meshwork was noted in one case using CD21 stain. C-MYC was expressed variably. CD3, bcl-2, MUM-1, CD30 and TDT were negative in all cases. EBER in situ hybridization was also all negative. FISH analyses using C-MYC, bcl-2 and bcl-6 break-apart probes were all negative. All cases had the 11q23.3 gain/11q24.3 loss pattern, and 11q23.3 amplification was found in one case. IgH and IRF4 break-apart probes analysis was also negative. All patients were alive with no disease after a follow-up of 4 to 19 months. Conclusion: BLL-11q is a rare lymphoma that resembles Burkitt lymphoma morphologically and phenotypically, but lacks C-MYC gene rearrangements. Instead, it has a chromosome-11q alteration characterized by proximal gains and telomeric losses. It's necessary to improve our understanding of BLL-11q to avoid misdiagnosis and missed diagnosis.


Assuntos
Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Adulto , Linfoma de Burkitt/genética , Aberrações Cromossômicas , Feminino , Genes myc/genética , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Biologia Molecular , Translocação Genética , Adulto Jovem
20.
Nat Commun ; 12(1): 3361, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099699

RESUMO

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma de Células B/genética , Linfoma não Hodgkin/genética , Inclusão em Parafina/métodos , Fixação de Tecidos/métodos , Translocação Genética , Biologia Computacional/métodos , Rearranjo Gênico , Genes bcl-2/genética , Genes myc/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Linfoma de Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Proteínas Proto-Oncogênicas c-bcl-6/genética , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
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