Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.624
Filtrar
1.
Leuk Res ; 95: 106387, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32535247

RESUMO

A relatively small subset of myeloid neoplasms involve rearrangements of cytoband 3q26.2. Such rearrangements are often in response to therapy and carry a poor prognosis. The ectopic expression of MECOM is the result of such translocations. To date, thirty-three t(3;8)(q26.2;q24) cases have been reported; we contribute two patients with confirmed MECOM and MYC rearrangements. Both patients presented with pancytopenia and were diagnosed with myelodysplastic/myeloproliferative disorders. In addition to translocation t(3;8), Patient 1 possessed a derivative chromosome 5, while Patient 2 possessed monosomy 7; neither patient's clonal abnormalities resolved in follow-up studies. Of the previous 33 cases, one exhibited 5q loss, while monosomy 7 was found in fifteen. These findings contribute to the small number of reported cases with t(3;8) translocations. We also speculate about the molecular mechanisms associated with this translocation.


Assuntos
Proteína do Locus do Complexo MDS1 e EVI1/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Idoso , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 7/genética , Genes myc/genética , Humanos , Masculino , Pessoa de Meia-Idade , Translocação Genética
2.
Am J Respir Crit Care Med ; 202(7): 962-972, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459537

RESUMO

Rationale: Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain.Objectives: In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island (n = 836).Methods: We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data.Measurements and Main Results: We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07; P = 6.62 × 10-8) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of TMEM9 in nasal airway epithelial cells and MROH3P in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased TMEM9 gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21; P = 5.03 × 10-6). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function.Conclusions: We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Asma/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 5/genética , Volume Expiratório Forçado/genética , Índios Norte-Americanos/genética , Pulmão/fisiopatologia , Adolescente , Asma/fisiopatologia , Brônquios/citologia , Estudos de Casos e Controles , Linhagem Celular , Criança , Imunoprecipitação da Cromatina , Mapeamento Cromossômico , Mucosa Esofágica/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Expressão Gênica , Humanos , Desequilíbrio de Ligação , Pulmão/fisiologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Miócitos de Músculo Liso , Mucosa Nasal/metabolismo , Polimorfismo de Nucleotídeo Único , Porto Rico , Locos de Características Quantitativas , Análise de Sequência de RNA , Sequenciamento Completo do Genoma , Adulto Jovem
4.
Int J Hematol ; 112(2): 238-242, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32246278

RESUMO

A 70-year-old male was referred to our hospital for marked thrombocytosis without anemia. The patient simultaneously presented with an MPL W515L mutation, one of the major driver mutations in essential thrombocythemia (ET), and deletion of 5q, a characteristic cytogenetic abnormality in myelodysplastic syndrome (MDS). Bone marrow examination showed a combination of both mature hyperlobulated megakaryocytes, as found in ET, and small hypolobulated megakaryocytes, typically found in MDS with del(5q). The present case is consistent with the recently proposed category of myeloid neoplasms with isolated del(5q) and an MPN driver mutation.


Assuntos
Mutação , Receptores de Trombopoetina/genética , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Idoso , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Humanos , Masculino , Megacariócitos/patologia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Trombocitemia Essencial/patologia , Organização Mundial da Saúde
5.
Nat Cell Biol ; 22(5): 526-533, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32251398

RESUMO

Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS)1. Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant2 within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients3. Here we show that patients who become resistant to LEN harbour recurrent variants of TP53 or RUNX1. LEN upregulated RUNX1 protein and function in a CRBN- and TP53-dependent manner in del(5q) cells, and mutation or downregulation of RUNX1 rendered cells resistant to LEN. LEN induced megakaryocytic differentiation of del(5q) cells followed by cell death that was dependent on calpain activation and CSNK1A1 degradation4,5. We also identified GATA2 as a LEN-responsive gene that is required for LEN-induced megakaryocyte differentiation. Megakaryocytic gene-promoter analyses suggested that LEN-induced degradation of IKZF1 enables a RUNX1-GATA2 complex to drive megakaryocytic differentiation. Overexpression of GATA2 restored LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for mutations that block LEN-induced megakaryocytic differentiation should identify patients who are resistant to LEN.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Cromossomos Humanos Par 5/genética , Lenalidomida/farmacologia , Megacariócitos/efeitos dos fármacos , Síndromes Mielodisplásicas/genética , Linhagem Celular , Cromossomos Humanos Par 5/efeitos dos fármacos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fator de Transcrição GATA2/genética , Células HEK293 , Humanos , Mutação/efeitos dos fármacos , Mutação/genética , Proteína Supressora de Tumor p53/genética
6.
Taiwan J Obstet Gynecol ; 59(1): 135-139, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039782

RESUMO

OBJECTIVE: We present prenatal diagnosis of concomitant distal 5q duplication and terminal 10q deletion in a fetus with intrauterine growth restriction (IUGR), congenital diaphragmatic hernia (CDH) and congenital heart defects (CHD). CASE REPORT: A 34-year-old, gravida 4, para 2, woman was referred for amniocentesis at 21 weeks of gestation because of advanced maternal age and IUGR. There was no congenital malformation in the family. Amniocentesis revealed a derivative chromosome 10 with an additional maternal on the terminal region of 10q. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from the cultured amniocytes revealed a result of arr 5q31.3q35.5 (142, 548, 354-180,696,806) × 3.0, arr 10q26.3 (132, 932, 808-135,434,178) × 1.0 [GRCh37 (hg19)] with a 2.50-Mb deletion of 10q26.3 encompassing 19 [Online Mendelian Inheritance in Man (OMIM)] genes and a 38.15-Mb duplication of 5q31.3-q35.5 encompassing 195 OMIM genes including four CDH candidate genes of NDST1, ADAM19, NSD1 and MAML1. The mother was found to have a karyotype of 46,XX,t(5; 10) (q31.3; q26.3). Therefore, the fetal karyotype was 46,XX,der(10)t(5; 10)(q31.3; q26.3)mat. Prenatal ultrasound showed IUGR, right CDH, transposition of great artery, double outlet of right ventricle and right atrial isomerism. The pregnancy was terminated, and a malformed fetus was delivered with facial dysmorphism. CONCLUSION: Fetuses with concomitant distal 5q duplication and terminal 10q deletion may present IUGR, CDH and CHD on prenatal ultrasound.


Assuntos
Anemia Macrocítica/diagnóstico , Retardo do Crescimento Fetal/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hérnias Diafragmáticas Congênitas/diagnóstico , Monossomia/diagnóstico , Adulto , Amniocentese , Anemia Macrocítica/embriologia , Anemia Macrocítica/genética , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Feminino , Retardo do Crescimento Fetal/genética , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Hérnias Diafragmáticas Congênitas/embriologia , Hérnias Diafragmáticas Congênitas/genética , Humanos , Monossomia/genética , Gravidez
7.
Dev Cell ; 52(4): 413-428.e6, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32097652

RESUMO

High levels of cancer aneuploidy are frequently associated with poor prognosis. To examine the relationship between aneuploidy and cancer progression, we analyzed a series of congenic cell lines that harbor single extra chromosomes. We found that across 13 different trisomic cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, we discovered that chromosomal instability activates cGAS/STING signaling but strongly suppresses invasiveness. By analyzing patient copy-number data, we demonstrate that specific aneuploidies are associated with distinct outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different aneuploidies can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, thereby linking genomic plasticity, phenotypic plasticity, and metastasis.


Assuntos
Aneuploidia , Movimento Celular , Instabilidade Cromossômica , Cromossomos Humanos Par 5/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Transição Epitelial-Mesenquimal , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/genética , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Iran Biomed J ; 24(1): 60-3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301695

RESUMO

Background: Mosaicism of a normal cell population and an unbalanced autosomal chromosome rearrangement is rarely seen. If the abnormal cell line contributes to a minor part of soma, the phenotype is expected to be normal. Case Report: We report a 29-year-old woman who had balance chromosomal translocation of 46,XX,t(5;21) with a two-year-old affected girl, characterized by mental retardation, dystrophia, hearing impartment, and dysphagia. Methods and Results: Cytogenetic investigation revealed a low mosaic unbalanced translocation of 46,XX,t(5;21)/ 46,XX, which was confirmed by fluorescence in situ hybridization analysis. Studying 200 metaphases and interphases of peripheral blood sample revealed 70% partial monosomy of 21q22 and partial trisomy of 5q(35.3) and 30% of normal pattern. Conclusion: In rare cases such as this study, parents with balanced translocation with no phenotypes may lead to a mosaic unbalanced translocation with abnormal phenotypes in offspring, which underscores the need for prenatal karyotyping and genetics counseling.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 5/genética , Citogenética , Hibridização in Situ Fluorescente , Mosaicismo , Translocação Genética/genética , Pré-Escolar , Humanos , Cariotipagem
9.
Cancer Genet ; 240: 66-72, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794935

RESUMO

Ependymomas are neuroepithelial tumors that differentiate along the ependymal cell lineage, a lining of the ventricles of the brain and the central canal of the spinal cord. They are rare in adults, but account for around 9% of brain tumors in children, where they usually have an aggressive course. Efficient stratification could lead to improved care but remains a challenge even in the genomic era. Recent studies proposed a multivariate classification system based on tumor location, age, and broad genomic findings like global patterns of methylation and copy number variants (CNVs). This system shows improved prognostic utility, but is relatively impractical in the routine clinical setting because it necessitates multiple diagnostic tests. We analyzed 13 intracranial grade II and III ependymoma specimens on a DNA microarray to identify discrete CNVs that could support the existing classification. The loss of chr22 and the gain of 5p15.31 were common throughout our cohort (6 and 11 cases, respectively). Other CNVs correlated well with the previously proposed classification system. For example, gains of chr20 were unique to PF-EPN-B tumors of the posterior fossa and may differentiate them from PF-EPN-A. Given the ease of detecting CNVs using multiple, clinically validated methods, these CNVs should be further studied to confirm their diagnostic and prognostic utility, for incorporation into clinical testing algorithms.


Assuntos
Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Ependimoma/diagnóstico , Neoplasias Infratentoriais/diagnóstico , Neoplasias Supratentoriais/diagnóstico , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 5/genética , Fossa Craniana Posterior/patologia , Diagnóstico Diferencial , Ependimoma/genética , Ependimoma/mortalidade , Ependimoma/patologia , Estudos de Viabilidade , Feminino , Humanos , Lactente , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/mortalidade , Neoplasias Infratentoriais/patologia , Masculino , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/mortalidade , Neoplasias Supratentoriais/patologia
10.
J Genet ; 982019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31544782

RESUMO

Although it is known that the parental carriers of chromosomal translocation are considered to be at high risk for spontaneous abortion and embryonic death, normal gestation and delivery remain possible. This study aims to investigate the genetic factors of a Chinese infant with multiple malformations and severe postnatal development retardation. In this study, the routine cytogenetic analysis, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) analysis were performed. Conventional karyotype analyses revealed normal karyotypes of all family members. CMA of the DNA of the proband revealed a 8.3 Mb duplication of 5q35.1-qter and a 6.9 Mb deletion of 11q24.3-qter. FISH analyses verified a paternal tiny translocation between the long arm of chromosomes 5 and 11. Our investigation serves to provide important information on genetic counselling for the patient and future pregnancies in this family. Moreover, the combined use of CMA and FISH is effective for clarifying pathogenically submicroscopic copy number variants.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 5/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Translocação Genética , Anormalidades Múltiplas/genética , Deleção Cromossômica , Duplicação Cromossômica/genética , Análise Citogenética , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Análise em Microsséries , Trissomia/genética , Trissomia/patologia
11.
Cells ; 8(9)2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514470

RESUMO

Induced pluripotent stem cells (iPSCs) have revolutionized the study of human diseases as they can renew indefinitely, undergo multi-lineage differentiation, and generate disease-specific models. However, the difficulty of working with iPSCs is that they are prone to genetic instability. Furthermore, genetically unstable iPSCs are often discarded, as they can have unforeseen consequences on pathophysiological or therapeutic read-outs. We generated iPSCs from two brothers of a previously unstudied family affected with the inherited retinal dystrophy choroideremia. We detected complex rearrangements involving chromosomes 12, 20 and/or 5 in the generated iPSCs. Suspecting an underlying chromosomal aberration, we performed karyotype analysis of the original fibroblasts, and of blood cells from additional family members. We identified a novel chromosomal translocation t(12;20)(q24.3;q11.2) segregating in this family. We determined that the translocation was balanced and did not impact subsequent retinal differentiation. We show for the first time that an undetected genetic instability in somatic cells can breed further instability upon reprogramming. Therefore, the detection of chromosomal aberrations in iPSCs should not be disregarded, as they may reveal rearrangements segregating in families. Furthermore, as such rearrangements are often associated with reproductive failure or birth defects, this in turn has important consequences for genetic counseling of family members.


Assuntos
Coroideremia/genética , Células-Tronco Pluripotentes Induzidas/patologia , Distrofias Retinianas/genética , Translocação Genética/genética , Diferenciação Celular/genética , Células Cultivadas , Reprogramação Celular/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 5/genética , Humanos , Cariótipo , Irmãos
12.
Genes (Basel) ; 10(8)2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374908

RESUMO

The incidence of thyroid cancer (TC), particularly well-differentiated forms (DTC), has been rising and remains the highest among endocrine malignancies. Although ionizing radiation (IR) is well established on DTC aetiology, other environmental and genetic factors may also be involved. DNA repair single nucleotide polymorphisms (SNPs) could be among the former, helping in explaining the high incidence. To further clarify the role of DNA repair SNPs in DTC susceptibility, we analyzed 36 SNPs in 27 DNA repair genes in a population of 106 DTCs and corresponding controls with the aim of interpreting joint data from previously studied isolated SNPs in DNA repair genes. Significant associations with DTC susceptibility were observed for XRCC3 rs861539, XPC rs2228001, CCNH rs2230641, MSH6 rs1042821 and ERCC5 rs2227869 and for a haplotype block on chromosome 5q. From 595 SNP-SNP combinations tested and 114 showing relevance, 15 significant SNP combinations (p < 0.01) were detected on paired SNP analysis, most of which involving CCNH rs2230641 and mismatch repair variants. Overall, a gene-dosage effect between the number of risk genotypes and DTC predisposition was observed. In spite of the volume of data presented, new studies are sought to provide an interpretability of the role of SNPs in DNA repair genes and their combinations in DTC susceptibility.


Assuntos
Reparo do DNA , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Cromossomos Humanos Par 5/genética , Ciclina H/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fatores de Transcrição/genética
13.
BMC Med Genomics ; 12(1): 116, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375103

RESUMO

BACKGROUND: Balanced structural variants are mostly described in disease with gene disruption or subtle rearrangement at breakpoints. CASE PRESENTATION: Here we report a patient with mild intellectual deficiency who carries a de novo balanced translocation t(3;5). Breakpoints were fully explored by microarray, Array Painting and Sanger sequencing. No gene disruption was found but the chromosome 5 breakpoint was localized 228-kb upstream of the MEF2C gene. The predicted Topologically Associated Domains analysis shows that it contains only the MEF2C gene and a long non-coding RNA LINC01226. RNA studies looking for MEF2C gene expression revealed an overexpression of MEF2C in the lymphoblastoid cell line of the patient. CONCLUSIONS: Pathogenicity of MEF2C overexpression is still unclear as only four patients with mild intellectual deficiency carrying 5q14.3 microduplications containing MEF2C are described in the literature. The microduplications in these individuals also contain other genes expressed in the brain. The patient presented the same phenotype as 5q14.3 microduplication patients. We report the first case of a balanced translocation leading to an overexpression of MEF2C similar to a functional duplication.


Assuntos
Cromatina/metabolismo , Deficiência Intelectual/genética , Criança , Pré-Escolar , Bandeamento Cromossômico , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Feminino , Duplicação Gênica , Humanos , Lactente , Recém-Nascido , Fatores de Transcrição MEF2/genética
14.
Rinsho Ketsueki ; 60(7): 800-809, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391370

RESUMO

In myeloid neoplasms, deletions of the long arm of chromosome 5 del(5q) and 7 (-7/del(7q) ) are common karyotypic abnormalities. The concurrence of del(5q) and -7/del(7q) accounts for poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Comprehensive analysis of copy number abnormalities and genetic mutations related to del(5q) and -7/del(7q) revealed previously cryptic pathophysiology, leading to frequent hemizygous/homozygous mutations and haploinsufficiency. In addition, detailed somatic mutations on chr5q were detected using whole-exome sequencing. CSNK1A1 and G3BP1 are located within the common deleted regions (CDRs) (5q31.1-5q33.1), and another driver gene DDX41 is present in the more telomeric region (5q35.3). All the genes mentioned above exhibited haploinsufficiency because of deletions, and low expression of G3BP1 and DDX41 correlated with poor survival. The related mutational events outside of chr5q, TP53 mutation is most frequently observed in del(5q) cases. Regarding -7/del(7q), 3 CDRs were located in 7q22, 7q34, and 7q35-36. Somatic mutations of the corresponding genes to each CDR (CUX1: 7q22, LUC7L2: 7q34, EZH2: 7q35-36) were identified, indicating that the loss of function or haploinsufficiency might result in the downstream pathological consequences. These recent findings have remarkably offered insights into genetic and clinical consequences in MDS/AML cases with del(5q) and -7/del(7q).


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 7/genética , Leucemia Mieloide Aguda/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética
15.
Cardiol Young ; 29(8): 1115-1117, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31331405

RESUMO

We report a rare association of interstitial deletion of 5p15.2-p13.3 with situs inversus, dextrocardia, L-loop of the ventricles, and transposition of great arteries: [I, L, L] Transposition of Great Arteries. We did not find such an association reported in the medical literature.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Dextrocardia/complicações , Situs Inversus/complicações , Transposição dos Grandes Vasos/complicações , Ecocardiografia Doppler em Cores , Feminino , Humanos , Recém-Nascido , Transposição dos Grandes Vasos/cirurgia
16.
Acta Haematol ; 142(2): 92-97, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085913

RESUMO

The platelet-derived growth factor receptor ß (PDGFRB) gene translocations lead to a spectrum of chronic myeloid neoplasms, frequently associated with eosinophilia. Clinical heterogeneity is associated with a molecular one. Here, we report a novel case of a patient harboring a t(5;8)(q33;p22) translocation, resulting in the PCM1/PDGFRB fusion. Conventional cytogenetics and RNA sequencing were performed to identify the chromosomes and the genes involved in the rearrangement, respectively. This study shows that the combination of different strategies is pivotal to fine-tune the diagnosis and the clinical management of the patient. After 1 year of treatment with imatinib, the patient achieves hematological and molecular remission. We present an attractive strategy to identify novel and/or cryptic fusions, which will be relevant for clinicians dealing with the diagnosis of the patients with myelodysplastic syndrome/myeloproliferative diseases with atypical manifestations.


Assuntos
Autoantígenos , Proteínas de Ciclo Celular , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas de Fusão Oncogênica , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Análise de Sequência de RNA , Autoantígenos/genética , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 5/metabolismo , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Translocação Genética
17.
BMJ Case Rep ; 12(4)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31005862

RESUMO

A patient with a diagnosis of myelodysplastic syndrome (MDS) with isolated 5q deletion underwent repeat bone marrow biopsy to assess haematological response after 6 months of initial lenalidomide therapy. Subsequent bone marrow biopsies revealed persistent MDS with del(5q) in addition to a small atypical mast cell population with >25% of mast cells with spindle-shaped morphology and immunohistochemistry characteristics consistent with mastocytosis. Molecular testing on the bone marrow was positive for cKIT D816V and the patient was diagnosed with systemic mastocytosis (SM) with an associated haematological neoplasm. MDS with SM is well known to be associated; however, to the best of our knowledge, only one prior case report identifies MDS with del(5q) and associated cKIT D816V positive mastocytosis. While the exact clonal origin of both chromosomal aberrations is unclear, this case illustrates the therapeutic efficacy of lenalidomide in a patient with MDS with del(5q) and rarely associated cKIT positive SM.


Assuntos
Anemia Macrocítica/complicações , Neoplasias Hematológicas/complicações , Mastocitose/complicações , Síndromes Mielodisplásicas/complicações , Anemia Macrocítica/diagnóstico , Anemia Macrocítica/genética , Biópsia , Medula Óssea/patologia , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Fatores Imunológicos/administração & dosagem , Lenalidomida/administração & dosagem , Masculino , Mastocitose/diagnóstico , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia
18.
Genet Epidemiol ; 43(5): 559-576, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31016765

RESUMO

While current genome-wide association analyses often rely on meta-analysis of study-specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega-imputation and mega-analysis) or study-specifically (meta-imputation and meta-analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age-related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis. From 27,448,454 genetic variants after 1,000-Genomes-based imputation, mega-imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta-imputation. For AMD signal detection (P < 5 × 10-8 ) in mega-imputed data, most loci were detected with mega-analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects and P-values were comparable across analyses. In meta-imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole-genome amplification (WGA) with study membership or after excluding studies with WGA-participants. For signal detection with multistudy IPD, we recommend mega-imputation and mega-analysis, with meta-imputation followed by meta-analysis being a computationally appealing alternative.


Assuntos
Predisposição Genética para Doença , Degeneração Macular/genética , Cromossomos Humanos Par 5/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
19.
Med Sci Monit ; 25: 1439-1451, 2019 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-30796769

RESUMO

BACKGROUND This study aimed to investigate susceptibility to Graves's disease and the association with the 5q32-33.1 region on chromosome 5 in a Chinese Han population. MATERIAL AND METHODS Eighty Chinese Han multiplex families included first-degree and second-degree relatives with Graves' disease. Eight microsatellite markers on chromosome 5 at the 5q32-33.1 region underwent linkage analysis and the association between the regions D5S1480-D5S2014 were studied. RESULTS The maximal heterogeneity logarithm of the odds (HLOD) score of D5S2090 was 4.29 (α=0.42) and of D5S2014 was 4.01 (α=0.34). A nonparametric linkage (NPL) score of 3.14 (P<0.001) was found for D5S2014. The D5S1480-D5S2014 region on chromosome 5 was associated with Graves' disease, with eight haplotype domains. There were significant differences in the sixth and eighth haplotype domains between patients with Graves' disease compared with normal individuals. Tagging single nucleotide polymorphisms (SNPs) of the sixth and eighth haplotype domains showed that individuals with SNP62 (rs12653715 G/C) who were GG homozygous had a significantly increased risk of Graves' disease compared GC heterozygous or CC homozygous individuals. The transmission disequilibrium test (TDT) indicated that SNP62 (rs12653715) and SNP63 (rs12653081) loci in the Janus kinase and microtubule interacting protein 2 (JAKMIP2) gene showed dominant transmission from heterozygous parents to the affected offspring, and SNPs in the secretoglobin family 3A member 2 (SCGB3A2) gene showed no transmission disequilibrium. The haplotype JAKMIP2-1 was identified as being particularly significant. CONCLUSIONS JAKMIP2 gene polymorphism require further study as potential risk factors for Graves' disease in the Chinese Han population.


Assuntos
Doença de Graves/genética , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Cromossomos , Cromossomos Humanos Par 5/genética , Grupos Étnicos/genética , Feminino , Ligação Genética/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Proteínas Supressoras de Tumor/metabolismo
20.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775878

RESUMO

Myelodysplastic syndromes (MDS) with basophilia or eosinophilia are very rare and portend poor prognoses. We present a rare patient who had MDS with excess blasts as well as peripheral basophilia and concurrent bone marrow (BM) basophilia/eosinophilia. She had a complex karyotype including 5q and 7q deletions; however, no oncogenic mutations were observed on next-generation sequencing of 54 genes known to be frequently mutated in acute myeloid leukemia/MDS. Peripheral basophilia resolved after decitabine treatment. Ours is the first report to describe a genome-wide analysis and the use of decitabine to successfully treat basophilia in an MDS patient with concurrent BM basophilia/eosinophilia.


Assuntos
Deleção Cromossômica , Eosinofilia/genética , Estudo de Associação Genômica Ampla/métodos , Síndromes Mielodisplásicas/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Basófilos/efeitos dos fármacos , Basófilos/patologia , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 7/genética , Decitabina/uso terapêutico , Eosinofilia/sangue , Eosinofilia/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA