Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.571
Filtrar
1.
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
2.
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
3.
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
4.
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
5.
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
6.
Mol Genet Genomic Med ; 7(4): e00591, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30697976

RESUMO

BACKGROUND: Platelet-derived growth factor receptor beta (PDGFRB) rearrangement has been reported in a number of patients with chronic eosinophilic leukemia (CEL), B-acute lymphoblastic leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia. Here, we report a case of CEL carrying a novel fusion gene involving PDGFRB and GRIP and coiled-coil domain containing 2 (GCC2). PATIENT AND METHODS: A 54-year-old man presenting with a cough and dyspnea was diagnosed with acute eosinophilic pneumonia. Cytogenetic analysis of the bone marrow revealed the presence of t(2;5)(q37;q31). Fluorescence in situ hybridization analysis in the peripheral blood leukocytes revealed the presence of a split signal at PDGFRB gene. Imatinib treatment was effective, and disappearance of t(2;5)(q37;q31) in the bone marrow was confirmed after three months of imatinib therapy. Whole-genome sequencing was performed in peripheral blood leukocytes collected before imatinib therapy. RESULTS: A novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and the presence of GCC2-PDGFRB was confirmed by PCR. CONCLUSION: This is the first case report demonstrating the GCC2 gene as a partner of PDGFRB in the pathogenesis of CEL.


Assuntos
Biomarcadores Tumorais/genética , Proteínas da Matriz do Complexo de Golgi/genética , Síndrome Hipereosinofílica/genética , Leucemia/genética , Proteínas de Fusão Oncogênica/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 5/genética , Humanos , Síndrome Hipereosinofílica/patologia , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Translocação Genética
7.
Mol Carcinog ; 58(6): 913-921, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30680798

RESUMO

The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer. However, causal variants in this region have not been fully uncovered. In this study, we intended to identify functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility in Chinese population. A targeted sequencing on 5p15.33 region was conducted in 400 NSCLC cases. We selected candidate variants by comparing genotypic frequency with data from 1000 Genomes Project, and their associations with NSCLC were validated in 985 cases and 970 controls. The relationships between risk variants and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays (EMSA) were performed to explore potential functions and reveal carcinogenic mechanisms. As a result, we identified 1478 variants through targeted sequencing and selected 17 candidates. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR = 1.34, 95%CI: 1.18-1.52, P = 7.78 × 10-6 ), rs10054203 (OR = 1.29, 95%CI: 1.13-1.46, P = 1.37 × 10-4 ), rs2736107 (OR = 1.28, 95%CI: 1.11-1.47, P = 5.14 × 10-4 ), and rs2853677 (OR = 1.23, 95%CI: 1.08-1.39, P = 0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P = 0.008 and 0.036, respectively). Mechanistically, the rs7726159-A increased TERT transcription through mediating allele-specific MYC binding. In conclusion, the functional variant rs7726159 confers lung cancer susceptibility might by affecting MYC binding and inducing telomere lengthening, which provides a new insight into the crucial role of telomere biology in tumorigenesis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Cromossomos Humanos Par 5/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Telômero/metabolismo , Células A549 , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , China , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-myc/metabolismo , Análise de Sequência de DNA , Telomerase/metabolismo , Homeostase do Telômero
8.
Blood Adv ; 2(24): 3637-3647, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30578281

RESUMO

Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, P meta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (P meta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.


Assuntos
Afro-Americanos/genética , Anemia Falciforme/patologia , Cromossomos Humanos Par 5/genética , Isoanticorpos/sangue , Alelos , Anemia Falciforme/genética , Anemia Falciforme/imunologia , Cromossomos Humanos Par 2/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo
9.
Pathol Res Pract ; 214(6): 919-923, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29496305

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive childhood leukemia characterized by an excess proliferation of cells of granulocytic and monocytic lineages. The WHO classifies JMML with the myelodysplastic/myeloproliferative neoplasms. Myelodysplasia in JMML is usually minimal to mild. Auer rods have never been reported in JMML. We present a 2-year-old boy with splenomegaly, leukocytosis, thrombocytopenia, anemia, and excess myeloblasts with easily seen Auer rods, and marked dysgranulopoiesis and dyserythropoiesis. Conventional cytogenetic analysis showed a sole abnormality of t(3;5)(q25;q35). Microarray analysis showed a terminal 21 Mb region of copy-neutral loss of heterozygosity on 19q. Disease-related somatic NRAS mutation was detected. This case represents an unusual JMML with Auer rods and marked myelodysplasia. These unusual histopathologic features may be related to the t(3;5)(q25;q35). A t(3;5) with variable breakpoints has been reported in a small proportion of acute myeloid leukemias and myelodysplastic syndromes. To our knowledge, this is the first JMML case reported with this translocation.


Assuntos
Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Translocação Genética/genética , Pré-Escolar , Humanos , Masculino
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(1): 60-63, 2018 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-29419862

RESUMO

OBJECTIVE To assess the value of BAC-on-Beads(BoBs) technology combined with conventional chromosomal karyotyping for reducing birth defects. METHODS For 690 women with singleton pregnancy and indication for prenatal diagnosis, aneuploidies of chromosomes 13, 18, 21, X and Y, in addition with 9 microdeletions and microduplications, were detected with the BoBs assay. And the results were compared with that of conventional karyotyping of amniocytes. RESULTS Karyotyping analysis attained a positive rate of 6.08% (42/690), which included 36 aneuploidies and 6 structural aberrations. The BoBs assay attained a detection rate of 5.95% (41/689). In addition to all chromosomal aneuploidies detected by conventional karyotyping, the Bobs assay has detected 3 cases with Xp22 region microdeletions, 1 case with 22q11 segment duplication, and 1 case with 5p15 microduplication. No balanced translocation or chromosomal polymorphisms was detected. CONCLUSION BoBs technique combined with conventional karyotyping is suitable for rapid diagnosis of a large number of prenatal cases and increasing the detection rate for fetal chromosomal abnormalities.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Doenças Fetais/genética , Diagnóstico Pré-Natal/métodos , Adulto , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos X/genética , Feminino , Doenças Fetais/diagnóstico , Humanos , Cariotipagem , Pessoa de Meia-Idade , Gravidez , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(1): 104-106, 2018 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-29419873

RESUMO

OBJECTIVE To analyze the clinical features and genetic mutations in a neonate with atypical Cri-du-chat syndrome, whom only featured with weak cry but had no dysmorphic facial features and congenital heart disease. METHODS G-banding karyotyping was performed on the child and her parents. The result was validated by fluorescence in situ hybridization (FISH). Chromosome microarray (CMA) was used to further delineate the mutation. RESULTS G-banding analysis suggested that the child had a karyotype of 46,XX,del(5)(p14p15), while both of his parents had a normal karyotype. FISH confirmed the absence of D5S23 and D5S721 at 5p15.2. A 25.7 Mb deletion was detected in the 5p15.33p14.1 region by CMA. CONCLUSION The phenotype of Cri-du-chat syndrome can vary significantly among patients, particularly in neonates, and can be easily mis-diagnosed. Combined cytogenetic and molecular analysis can identify the missing fragments with greater precision.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Síndrome do Miado do Gato/genética , Análise Citogenética/métodos , Bandeamento Cromossômico , Síndrome do Miado do Gato/diagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariótipo , Cariotipagem
12.
Epilepsia ; 59(2): 381-388, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29266188

RESUMO

OBJECTIVE: To investigate the significance of variation in ADGRV1 (also known as GPR98, MASS1, and VLGR1), MEF2C, and other genes at the 5q14.3 chromosomal locus in myoclonic epilepsy. METHODS: We studied the epilepsy phenotypes of 4 individuals with 5q14.3 deletion and found that all had myoclonic seizures. We then screened 6 contiguous genes at 5q14.3, MEF2C, CETN3, MBLAC2, POLR3G, LYSMD3, and ADGRV1, in a 95-patient cohort with epilepsy and myoclonic seizures. Of these genes, point mutations in MEF2C cause a phenotype involving seizures and intellectual disability. A role for ADGRV1 in epilepsy has been proposed previously, based on a recessive mutation in the Frings mouse model of audiogenic seizures, as well as a shared homologous region with another epilepsy gene, LGI1. RESULTS: Six patients from the myoclonic epilepsy cohort had likely pathogenic ultra-rare ADGRV1 variants, and statistical analysis showed that ultra-rare variants were significantly overrepresented when compared to healthy population data from the Genome Aggregation Database. Of the remaining genes, no definite pathogenic variants were identified. SIGNIFICANCE: Our data suggest that the ADGRV1 variation contributes to epilepsy with myoclonic seizures, although the inheritance pattern may be complex in many cases. In patients with 5q14.3 deletion and epilepsy, ADGRV1 haploinsufficiency likely contributes to seizure development. The latter is a shift from current thinking, as MEF2C haploinsufficiency has been considered the main cause of epilepsy in 5q14.3 deletion syndrome. In cases of 5q14.3 deletion and epilepsy, seizures likely occur due to haploinsufficiency of one or both of ADGRV1 and MEF2C.


Assuntos
Epilepsias Mioclônicas/genética , Receptores Acoplados a Proteínas-G/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Cromossomos Humanos Par 5/genética , Estudos de Coortes , Epilepsias Mioclônicas/complicações , Haploinsuficiência , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Fatores de Transcrição MEF2/genética , Masculino , Mutação Puntual , RNA Polimerase III/genética , Síndrome
13.
Cytogenet Genome Res ; 153(1): 22-28, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29141250

RESUMO

A 17-year-old girl presented with a distinct phenotype mainly featuring craniofacial dysmorphism, including a disproportioned large, round, elongated face; hypertelorism; deep-set eyes with short palpebral fissures; obesity (BMI 37), and a neuropsychiatric disorder with high-functioning autism. Postnatal conventional cytogenetic analyses from peripheral blood revealed a mosaic small supernumerary marker chromosome (sSMC) with a mos 47,XX,+mar[7]/46,XX[43] karyotype. By cenM-FISH technique, the sSMC was identified as a ring derivative of chromosome 5. Metaphase FISH analysis with a set of dedicated probes defined its origin from the pericentromeric region of chromosome 5, including the NIPBL gene at 5p13.2. Such sSMCs, exceedingly rare in the literature, underlie proximal trisomy 5p. In order to delineate a core phenotype of proximal trisomy 5p, we compared our patient's features with those of 6 patients found in the literature with similar der(5) chromosomes. Furthermore, a dozen individuals with 5p13 (micro)duplication syndrome was compared and discussed. We identified highly distinctive craniofacial dysmorphism, obesity, and intellectual disability and/or autism spectrum disorder as typical features of proximal 5p trisomy. In the critical region (band 5p13), the NIPBL gene is likely to be a major determinant of the neurobehavioral phenotype, and its presence at the sSMC level may be relevant to predict clinical outcome.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 5/genética , Trissomia/genética , Adolescente , Transtorno Autístico/genética , Anormalidades Craniofaciais/genética , Feminino , Humanos , Proteínas/genética
15.
J Huazhong Univ Sci Technolog Med Sci ; 37(5): 807-810, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29058300

RESUMO

We report one case of pediatric acute myeloid leukemia type 2 (AML-M2) who presented with karyotypic aberration of trisomy 21 with the t(5;11) chromosomal translocation. The patient achieved complete remission after two cycles of chemotherapy of daunorubicin, cytarabine and etoposide. Then, follow-up cytogenetic analysis from bone marrow cell cultures demonstrated a normal karyotype of 46, XY. After 9 years, the patient relapsed and the karyotypic abnormalities of trisomy 21 with t(5;11) reappeared. It was concluded that trisomy 21 with t(5; 11) is a new unfavorable cytogenetic aberration in AML-M2.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Síndrome de Down/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Aberrações Cromossômicas , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Indução de Remissão , Translocação Genética
16.
Semin Hematol ; 54(3): 159-166, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28958290

RESUMO

Myelodysplastic syndrome (MDS) with deletion 5q (del(5q)) is a distinct clinical and pathological disease subset that is exquisitely sensitive to lenalidomide for the treatment of red blood cell transfusion-dependent anemia. Although lenalidomide has erythropoeitic promoting activity in MDS without del(5q) (non-del(5q) MDS), the frequency of response to treatment is lower and relates to biologically separate drug effects. In del(5q) MDS, lenalidomide suppresses the malignant clone to restore effective erythropoiesis by virtue of synthetic lethality, arising from cereblon-dependent degradation of haplodeficient proteins encoded within the commonly deleted region of the chromosome 5q deletion. In contrast, in non-del(5q) MDS, lenalidomide restores effective erythropoiesis via enhancement of erythropoietin (EPO) receptor-initiated transcriptional response arising from the assembly of signaling-competent receptor complexes within membrane lipid raft domains. Recently, large phase III clinical studies have explored the role of lenalidomide, alone and in combination with, erythropoiesis-stimulating agents showing additive improvement in erythroid responses. Herein, we will describe the mechanisms of lenalidomide action in MDS and pivotal clinical studies testing the benefit of lenalidomide in both del(5q) and non-del(5q) MDS. Furthermore, we discuss evidence-based strategies to incorporate lenalidomide into the treatment algorithm for patients with MDS.


Assuntos
Cromossomos Humanos Par 5/genética , Fatores Imunológicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Deleção Cromossômica , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Lenalidomida , Síndromes Mielodisplásicas/patologia , Talidomida/administração & dosagem , Talidomida/farmacologia , Talidomida/uso terapêutico
17.
Cell Rep ; 20(11): 2556-2564, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28903037

RESUMO

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.


Assuntos
Cromossomos Humanos Par 5/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Elongação da Transcrição/genética , Alelos , Diploide , Epigênese Genética , Epigenômica , Loci Gênicos , Humanos , Proteínas Nucleares/metabolismo , Mapeamento Físico do Cromossomo , Prognóstico , Ligação Proteica , Fatores de Risco , Elongação da Transcrição Genética , Resposta a Proteínas não Dobradas/genética
18.
Ann Clin Lab Sci ; 47(4): 466-473, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28801374

RESUMO

OBJECTIVE: Myeloid sarcoma (MS) is defined in the World Health Organization classification as a tumor mass consisting of myeloblasts with or without maturation and involving any anatomic site other than the bone marrow. We present a case of MS developing in a patient with 5q- myelodysplastic syndrome (MDS) and review the relevant literature. METHODS: A 77-year-old woman with recent diagnosis of MDS associated with del(5q) presented with symptoms and signs attributable to a mass involving the T8 vertebra. Biopsy of the spinal mass was performed and the specimen was analyzed using routine hematoxylin-eosin stain, immunohistochemical methods, and fluorescence in situ hybridization (FISH). RESULTS: Microscopic examination revealed an infiltrate of intermediate-large cells with basophilic cytoplasm and nuclei containing occasional prominent nucleoli. Immunohistochemical analysis showed that the neoplastic cells were positive for CD4, CD43, CD45, CD68, and CD117, and negative for B- and T-cell antigens supporting the diagnosis of MS. Fluorescence in situ hybridization of the spinal mass showed del(5q) in the neoplastic cells. CONCLUSION: Although the 5q- syndrome is a clinically indolent form of MDS, a small subset of patients may develop MS as illustrated in this patient. The relevant literature is also reviewed.


Assuntos
Anemia Macrocítica/genética , Cromossomos Humanos Par 5 , Sarcoma Mieloide/genética , Idoso , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Prognóstico
19.
Genes Chromosomes Cancer ; 56(12): 841-845, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28758277

RESUMO

We present a new endometrial stromal sarcoma (ESS)-associated genomic rearrangement involving chromosome arms 5p and 6p and leading to the formation of a BRD8-PHF1 fusion gene. The PHF1 (PHD finger protein 1) gene, from 6p21, is known to be rearranged in ESS in a promiscuous way inasmuch as it has been shown to recombine with JAZF1, EPC1, MEAF6, and now also with BRD8, in tumors of this type. In all rearrangements of PHF1, including the present one, a recurrent theme is that the entire coding part of PHF1 constitutes the 3' end of the fusion. BRD8 (bromodomain containing 8) encodes a protein which is involved in regulation of protein acetylation and/or histone acetyl transferase activity. All the genetic fusions identified so far in ESS appear to recombine genes involved in transcriptional regulation, that is, polycomb group complex-mediated and aberrant methylation/acetylation genes. This adds to the likelihood that the new BRD8-PHF1 shares the same pathogenetic mechanism as the other ESS-specific rearrangements.


Assuntos
Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Proteínas de Fusão Oncogênica/genética , Proteínas do Grupo Polycomb/genética , Receptores dos Hormônios Tireóideos/genética , Sarcoma do Estroma Endometrial/genética , Células Cultivadas , Cromossomos Humanos Par 5/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Fusão Oncogênica , Proteínas de Fusão Oncogênica/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Sarcoma do Estroma Endometrial/patologia
20.
Orphanet J Rare Dis ; 12(1): 124, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28676062

RESUMO

Spinal muscular atrophy linked to chromosome 5q (SMA) is a recessive, progressive, neuromuscular disorder caused by bi-allelic mutations in the SMN1 gene, resulting in motor neuron degeneration and variable presentation in relation to onset and severity. A prevalence of approximately 1-2 per 100,000 persons and incidence around 1 in 10,000 live births have been estimated with SMA type I accounting for around 60% of all cases. Since SMA is a relatively rare condition, studies of its prevalence and incidence are challenging. Most published studies are outdated and therefore rely on clinical rather than genetic diagnosis. Furthermore they are performed in small cohorts in small geographical regions and only study European populations. In addition, the heterogeneity of the condition can lead to delays and difficulties in diagnosing the condition, especially outside of specialist clinics, and contributes to the challenges in understanding the epidemiology of the disease. The frequency of unaffected, heterozygous carriers of the SMN1 mutations appears to be higher among Caucasian and Asian populations compared to the Black (Sub-Saharan African ancestry) population. However, carrier frequencies cannot directly be translated into incidence and prevalence, as very severe (death in utero) and very mild (symptom free in adults) phenotypes carrying bi-allelic SMN1 mutations exist, and their frequency is unknown. More robust epidemiological data on SMA covering larger populations based on accurate genetic diagnosis or newborn screening would be helpful to support planning of clinical studies, provision of care and therapies and evaluation of outcomes.


Assuntos
Atrofia Muscular Espinal/epidemiologia , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Incidência , Masculino , Atrofia Muscular Espinal/etnologia , Prevalência , Proteína 1 de Sobrevivência do Neurônio Motor/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA