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1.
In Vivo ; 34(3 Suppl): 1633-1636, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503822

RESUMO

In a previous study, we identified a 117 base severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 Orf1b gene in non-structural protein 14 (NSP14), which is an exonuclease and NSP15, an endoribonuclease. In the current study we compared the human genome with other viral genomes to determine some of the characteristics of human sequences found in the latter. Most of the viruses had human sequences, but they were short. Hepatitis A and St Louis encephalitis had human sequences that were longer than the 117 base SARS-Cov-2 sequence, but they were in non-coding regions of the human genome. The SARS-Cov-2 sequence was the only long sequence found in a human gene (NTNG1). The related coronaviruses SARS-Cov had a 41 BP human sequence on chromosome 3 that was not part of a human gene, and MERS had no human sequence. The 117 base SARS-CoV-2 human sequence is relatively close to the viral spike sequence, separated only by NSP16, a 904 base sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. We have no explanation for the NSP14 and NSP15 SARS-Cov-2 sequences we observed here or how they might relate to infectiousness. Further studies are warranted.


Assuntos
Betacoronavirus/genética , Exorribonucleases/genética , Genoma Viral , Vírus da SARS/genética , Proteínas não Estruturais Virais/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3/genética , Vírus de DNA/genética , Proteínas Ligadas por GPI/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Netrinas/genética , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Proteínas Virais/genética
2.
Invest Ophthalmol Vis Sci ; 61(3): 31, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32186672

RESUMO

Purpose: A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in patients who survived 5 years following enucleation. Methods: A retrospective analysis was performed in 583 primary UM cases, enucleated at the Leiden University Medical Center between 1983 and 2013. Univariable and multivariable Cox regression analyses were performed in the total cohort and separately in those surviving more than 5 years (n = 297). Results: In the total cohort, the median age was 62.6 years, and the median tumor diameter was 12.0 mm. Monosomy 3 was detected in 53% of cases and gain of 8q in 47%. In the cohort surviving 5 years, the median age was 59.5 years, and the median tumor diameter was 11.0 mm. Monosomy 3 and gain of 8q were detected in 33% and 31% of cases, respectively. In the total cohort, male gender (P = 0.03), tumor diameter (P < 0.001), mitotic count (P < 0.001), extravascular matrix loops (P = 0.03), extraocular growth (P < 0.001), and gain of 8q (P < 0.001) were independently associated with UM-related death. In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P < 0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death. Using a multivariable analysis, only male gender (P = 0.03) and gain of 8q (P = 0.01) remained significant. Conclusions: Predictors of UM-related death change over time. Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on.


Assuntos
Enucleação Ocular , Melanoma/mortalidade , Melanoma/cirurgia , Neoplasias Uveais/mortalidade , Neoplasias Uveais/cirurgia , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
3.
PLoS Genet ; 16(2): e1008590, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32053595

RESUMO

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development.


Assuntos
Encéfalo/embriologia , Cromossomos Humanos Par 3/genética , Proteínas de Drosophila/genética , Desenvolvimento Embrionário/genética , Deficiência Intelectual/genética , Complexo Proteico Nuclear de Ligação ao Cap/genética , Proteínas de Xenopus/genética , Animais , Apoptose/genética , Encéfalo/patologia , Ciclo Celular/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Embrião não Mamífero , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Deficiência Intelectual/patologia , Complexo Proteico Nuclear de Ligação ao Cap/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis
4.
BMC Med Genet ; 21(1): 26, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028920

RESUMO

BACKGROUND: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications. METHODS: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed. RESULTS: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3). CONCLUSIONS: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.


Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Lisencefalia/genética , Neurônios/patologia , Translocação Genética/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Moléculas de Adesão Celular/genética , Movimento Celular/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 3/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/fisiopatologia , Hibridização Genômica Comparativa , Contactinas/genética , Feminino , Dosagem de Genes/genética , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Lisencefalia/diagnóstico , Lisencefalia/fisiopatologia , Meiose/genética , Proteínas Associadas aos Microtúbulos/genética , Neurônios/metabolismo , Fenótipo , Trissomia/genética
5.
Cancer Sci ; 111(4): 1385-1391, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31957195

RESUMO

Cancer studies primarily focus on the characterization of the key driver genes and the underlying pathways. However, the contribution of other cancer-associated genes located in the genomic neighborhood of the driver genes could help to understand further aspects of cancer progression. Given the frequent involvement of chromosome 3 in multiple human cancers, in particular in the form of the prognostically highly relevant monosomy 3 in uveal melanoma (UM), we investigated the cumulative impact of cancer-associated genes on chromosome 3. Our analysis showed that these genes are enriched with repetitive elements with genes surrounded by distinctive repeats (MIR, hAT-Charlie, ERVL-MaLR, LINE-2, and simple/low complexity) in the promoter being more precisely associated with cancer-related pathways than the ones with major transposable elements (SINE/Alu and LINE-1). Additionally, these genes showed strong intrachromosomal chromatin interactions in 3D nuclear organization. Further investigations revealed a genomic hotspot in the vicinity of BAP1 locus, which is affected in 27 types of different cancers and contains abundant noncoding RNAs that are often expressed in a tissue-specific manner. The cross-species comparison of these cancer-associated genes revealed mostly a shared synteny in closer primates. However, near to the BAP1 locus signs of chromosomal inversions were observed during the course of evolution. To our knowledge, this is the first study to characterize the entire genomic neighborhood of cancer-associated genes located on any single chromosome. Based on our results, we hypothesize that monosomy of chromosome 3 will have important clinical and molecular consequences in the respective diseases and in particular in UM.


Assuntos
Cromatina/genética , Evolução Molecular , Melanoma/genética , Sequências Repetitivas de Ácido Nucleico/genética , Neoplasias Uveais/genética , Elementos Alu/genética , Animais , Inversão Cromossômica/genética , Cromossomos Humanos Par 3/genética , Biologia Computacional , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Melanoma/patologia , Primatas/genética , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/patologia
6.
J Assist Reprod Genet ; 36(12): 2533-2539, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720922

RESUMO

RESEARCH QUESTION: Can preimplantation genetic testing for structural rearrangement (PGT-SR) with next-generation sequencing (NGS) be used to infertile patients carrying small supernumerary marker chromosomes (sSMCs)? DESIGN: In this study, two infertile patients carrying ring sSMCs were recruited. Different molecular cytogenetic techniques were performed to identify the features of the two sSMCs, followed by clinical PGT-SR cycles. RESULTS: The results of G-banding and FISH showed that patient 1's sSMC originated from the 8p23-p10 region, with a resulting karyotype of [ 47,XY, del(8)(p23p10), +r(8)(p23p10).ish del(8)(CEP8+,subtle 8p+,subtle 8q+),r(8)(CEP8+,subtle 8p-,subtle 8q-)[55/60].arr(1-22) ×2,(X,Y)×1]. The sSMC of patient 2 was derived from chromosome 3 and further microdissection with next-generation sequencing (MicroSeq) revealed it contained the region of chromosome 3 between 93,504,855 and 103,839,892 bp (GRCh37), which involved 52 known genes. So the karyotype of patient 2 was 47,XX, +mar.ish der(3)(CEP3+,subtle 3p-,subtle 3q-)[49/60].arr[GRCh37] 3q11.2q13.1(93,500,001_103,839,892) ×3(0.5). PGT-SR with NGS was performed to provide reproductive guidance for the two patients. For patient 1, four balanced euploid embryos and four embryos with partial trisomy/monosomy of (8p23.1-8p11.21) were obtained, and a balanced euploid embryo was successfully implanted and had resulted in a healthy baby. For patient 2, an embryo with monosomy of sex chromosomes and another embryo with a duplication at (3q11-q13.1), neither of which was available for implantation. CONCLUSIONS: The identification of the origins and structural characteristics of rare sSMCs should rely on different molecular cytogenetic techniques. PGT-SR is an alternative fertility treatment for these patients carrying sSMCs. This study may provide directions for the assisted reproductive therapy for infertile patients with sSMC.


Assuntos
Aberrações Cromossômicas , Análise Citogenética , Testes Genéticos , Trissomia/genética , Adulto , Cromossomos/genética , Cromossomos Humanos Par 3/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Infertilidade/genética , Infertilidade/patologia , Cariótipo , Cariotipagem , Masculino , Mosaicismo , Trissomia/patologia
7.
Taiwan J Obstet Gynecol ; 58(6): 864-868, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31759544

RESUMO

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 3. CASE REPORT: A 36-year-old woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+mar[6]/46,XX[18]. The mother's karyotype was 47,XX,+mar[4]/46,XX[46]. The father's karyotype was 46.XY. Array comparative genomic hybridization (aCGH) analysis of uncultured amniocytes revealed a result of arr 3q11.1q12.1 (93,575,285-98,956,687) × 2-3 [GRCh37 (hg19)]. Prenatal ultrasound findings were unremarkable. The parents elected to continue the pregnancy, and a 2470-g female baby was delivered at 37 weeks of gestation without phenotypic abnormalities. The cord blood had a karyotype of 47,XX,+mar[8]/46,XX[32]. aCGH analysis of cord blood revealed a result of arr 3q11.1q11.2 (93,649,973-97,137,764) × 2.4 [GRCh37 (hg19)] with a log2 ratio of 0.25 and a 30-40% mosaicism for 3.488-Mb dosage increase in 3q11.1-q11.2 encompassing four [Online Mendelian Inheritance in Man (OMIM)] genes of PROS1, ARL13B, NSUN3 and EPHA6. Metaphase fluorescence in situ hybridization (FISH) analysis confirmed 30% (6/20 cells) mosaicism for the sSMC(3) in the blood lymphocytes. CONCLUSION: aCGH and FISH analyses are useful for perinatal investigation of a prenatally detected sSMC.


Assuntos
Amniocentese/métodos , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 3/genética , Doenças Fetais/diagnóstico , Mosaicismo , Diagnóstico Pré-Natal/métodos , Adulto , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa , Feminino , Doenças Fetais/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez
8.
Stem Cell Res ; 40: 101545, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31472451

RESUMO

Here we describe the generation and characterization of the human induced pluripotent stem cell (iPSC) lines from urine-derived cells (UCs) from two patients with unbalanced chromosomal translocation t(3,22)(q28;q13.3). The iPSC lines retain the original chromosome abnormality, express pluripotency markers and bear differentiation potential.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Translocação Genética , Diferenciação Celular , Linhagem Celular , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 3 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Cariótipo , Masculino
9.
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
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 813-816, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400135

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with ultrasonographic abnormality. METHODS: Chromosomal karyotyping and array comparative genomic hybridization (array-CGH) analysis were applied for the diagnosis. Peripheral blood samples were also taken from the parents for chromosome karyotyping analysis. RESULTS: The fetal karyotype showed additional material of unknown-origin attached to Yq. Array CGH analysis confirmed that the material was derived from 3q22.1q29. The father was found to carry a balanced translocation 46, X, t(Y;3)(q12;q23) (which was diagnosed as 46,XY,Y≥18 elsewhere), whilst the mother was found to be normal. CONCLUSION: 3q partial trisomy may present as malformation of multiple systems. Combination of chromosome karyotyping and array-CGH can provide reliable diagnosis for fetuses with abnormalities by ultrasonography.


Assuntos
Cromossomos Humanos Par 3/genética , Diagnóstico Pré-Natal , Trissomia , Hibridização Genômica Comparativa , Feminino , Feto , Humanos , Cariotipagem , Masculino , Gravidez
11.
J Hum Genet ; 64(10): 1005-1014, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31311986

RESUMO

Complex rearrangements of chromosomes 3 and 9 were found in a patient presenting with severe epilepsy, developmental delay, dysmorphic facial features, and skeletal abnormalities. Molecular cytogenetic analysis revealed 46,XX.ish der(9)(3qter→3q28::9p21.1→9p22.3::9p22.3→9qter)(RP11-368G14+,RP11-299O8-,RP11-905L2++,RP11-775E6++). Her dysmorphic features are consistent with 3q29 microduplication syndrome and inv dup del(9p). Trio-based WES of the patient revealed no pathogenic single nucleotide variants causing epilepsy, but confirmed a 3q28q29 duplication involving FGF12, which encodes fibroblast growth factor 12. FGF12 positively regulates the activity of voltage-gated sodium channels. Recently, only one recurrent gain-of-function variant [NM_021032.4:c.341G>A:p.(Arg114His)] in FGF12 was found in a total of 10 patients with severe early-onset epilepsy. We propose that the patient's entire FGF12 duplication may be analogous to the gain-of-function variant in FGF12 in the epileptic phenotype of this patient.


Assuntos
Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Fatores de Crescimento de Fibroblastos/genética , Transtornos do Neurodesenvolvimento/genética , Espasmos Infantis/genética , Adolescente , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 9 , Variações do Número de Cópias de DNA , Feminino , Duplicação Gênica , Humanos , Lactente , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Espasmos Infantis/fisiopatologia , Translocação Genética , Sequenciamento Completo do Exoma
12.
Mol Biol Rep ; 46(4): 4323-4332, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31250359

RESUMO

From the literature review, there seem to be no studies conducted on infection caused by Helicobacter pylori in patients with gastric MALT lymphoma in the KSA region. The present research is an attempt to understand the prevalence of patients infected with H. pylori in the selected region and the role of allelic imbalance of chromosome 3p regions to understand the clinical manifestations and features associated with MALT lymphomagenesis. The researcher analyzed the frequency of infection in patients from the region of Saudi Arabia by examining the data collected from hospitals and biopsy tissue samples as per the recommended protocol. The endoscopic diagnosis was performed to collect biopsy samples. Histology and AP-PCR DNA fingerprinting analyses were performed from the endoscopic gastric mucosal biopsies collected from patients with associated gastric MALT lymphoma. The existence of H. pylori was examined based on the results of gastric mucosal biopsies stained with hematoxylin-eosin (H&E) and Steiner's silver stains. MALT, MALT lymphoma tissue samples and H. pylori-positive chronic gastritis were examined for LOH at chromosome 3p24 using standard procedures and techniques. The findings of the paper revealed the H. pylori was found to be positive in 17% of the cases significantly high among the age group of 31-50 years. Patients with MALT, MALT lymphoma, and H. pylori-associated gastritis presented features such as lymphocyte accumulation, vacuolation, Peyer's patch appearance, and lymphatic follicles. H. pylori were found to appear as a dense colored accumulated mass in the gastric epithelial layer. The findings from AP-PCR generated DNA fingerprints revealed intense band including two prominent bands in MALT lymphoma. Among other loci, 3p24 was the only one locus that showed high percentages of LOH as reported earlier in all cancer-related cases. The findings of this research paper empower the fact that allelic imbalances play a vital role in the development of MALT lymphoma. However, future researches should be conducted to identify the chromosome regions of the AP-PCR generated DNA fingerprints of human gastric MALT lymphoma in order to confirm this proposition.


Assuntos
Infecções por Helicobacter/epidemiologia , Helicobacter pylori/genética , Linfoma de Zona Marginal Tipo Células B/microbiologia , Adulto , Cromossomos/genética , Cromossomos Humanos Par 3/genética , Feminino , Mucosa Gástrica , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Prevalência , Prognóstico , Arábia Saudita/epidemiologia , Estômago , Gastropatias/genética , Gastropatias/microbiologia
13.
J Clin Lab Anal ; 33(8): e22961, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31218758

RESUMO

BACKGROUND: Clinically, 90%-95% of cases of CML have the characteristic t(9;22) (q34.1;q11.2) translocation that leads to the Philadelphia (Ph) chromosome. Rarely, patients with CML can present directly in a blast crisis (BC). While most blast crises are of myeloid origin, myeloid BC with ALL-like morphologic features and Ph-positive acute myeloid leukemia (AML) is rare, especially at the time of CML diagnosis. CASE PRESENTATION: A 20-year-old man presented with Ph chromosome-positive AML mimicking acute lymphocytic leukemia (ALL). Bone marrow (BM) aspiration revealed AML with ALL-like morphologic features. The results of the immunophenotypic analysis suggested AML. Cytogenetic analysis of the BM cells revealed a 46,XY,t(3;14)(q21;q32),t(9;22)(q34;q11.2)[20] karyotype. Thus, we called the condition AML mimicking ALL. The patient was diagnosed with myeloid BC based on the combination of clinical, cytologic, and cytogenetic studies. CONCLUSION: To date, no case reports of a patient diagnosed with CML BC presented with Ph chromosome-positive AML mimicking ALL have been reported. We present the case given its rarity, easy misdiagnosis, and poor prognosis. It is important to combine clinical, cytologic, and cytogenetic analyses in distinguishing CML BC from de novo AML with the t(9;22),and further cases should be accumulated to explore how to improve the prognosis of the patients.


Assuntos
Crise Blástica/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Translocação Genética , Adulto , Crise Blástica/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 9/genética , Diagnóstico Diferencial , Humanos , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Adulto Jovem
14.
BMC Med Genomics ; 12(1): 85, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196198

RESUMO

BACKGROUND: The 3q duplication syndrome is a result of duplication of a large fragment of the long arm of chromosome 3, mainly 3q21-qter, and in most cases it is diagnosed only after birth. The phenotypic consequences resulting from genetic imbalance are an important source of information for genetic counselling, especially in prenatal diagnostics. However, in most cases it is impossible to define them precisely because the final clinical presentation is a result of an overlap, usually due to different sizes of deletions and/or duplications not only chromosome 3 but also of translocation partner chromosome. In this article, we present a prenatal diagnosis of the 3q duplication syndrome in a foetus, arising from a balanced insertion ins (7,3)(q21.2;q12.3q29) carried by the mother. CASE PRESENTATION: The article presents a case of a 29-year-old woman referred to the Genetic Outpatient Clinic for consultation in the 12th week of her fifth pregnancy with a diagnosis of generalised hydrops foetalis. The analysis of karyotype using GTG technique and FISH allowed diagnosis of a balanced aberration in the mother, and determined the type of chromosomal rearrangement, which allowed the identification of the origin of the additional genetic material in the foetus and the previous malformed child of the same couple. The use of molecular karyotyping techniques (FISH and aCGH) allowed a precise determination of the size of the imbalanced fragments in the affected siblings. CONCLUSIONS: The aCGH technique is particularly valuable for the diagnostics of submicroscopic deletions and duplications, if no imbalanced chromosomal aberrations are detected by routine cytogenetic tests. It is also a valuable technique for identifying and fully characterizing genetic material of unknown origin, which can't be identified using routine cytogenetic techniqes. However, it does not allow identification of balanced aberrations in carriers.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal , Trissomia/diagnóstico , Adulto , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 3/genética , Feminino , Humanos , Cariótipo , Gravidez , Trissomia/genética
15.
Carcinogenesis ; 40(7): 819-827, 2019 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-31125406

RESUMO

Cancer is a complex disease, which may involve multiple tumor susceptibility genes that mediate the occurrence and development of tumor molecular events. This study aimed to identify new genetic loci using genome-wide linkage analysis and whole-exome sequencing in a rare, large multi-cancer pedigree recently found in China. We performed high-throughput single-nucleotide polymorphism (SNP) array and linkage analyses of 24 core members of this pedigree and found that the disease susceptibility locus in the multi-cancer pedigree was mapped to chromosome 3q24-26. We also used microsatellites to further validate the results of the SNP locus linkage analysis. Furthermore, we sequenced the whole exome of three members in this pedigree and identified a novel mutant of transforming growth factor ß stimulated clone 22 domain family, member 2 (TSC22D2, c.-91T-C) cosegregated with the cancer phenotype. This change was at a highly conserved position, and the exome results were validated using linkage analysis. Moreover, we found the histone H4 transcription factor (HINFP) binds to the promoter region of TSC22D2 and may regulate its transcription. In conclusion, our findings are of great significance to the early pathogenesis of tumors and contribute to the search for molecular targets for the early prevention and treatment of tumors.


Assuntos
Cromossomos Humanos Par 3/genética , Proteínas de Ligação a DNA/genética , Loci Gênicos , Predisposição Genética para Doença , Neoplasias/genética , Fatores de Transcrição/genética , Adulto , China , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Ligação Genética , Células HEK293 , Haplótipos , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/metabolismo , Sequenciamento Completo do Exoma
16.
Genes Brain Behav ; 18(6): e12580, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31099175

RESUMO

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único , Transtornos Relacionados ao Uso de Substâncias/genética , Estriado Ventral/fisiopatologia , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 3/genética , Loci Gênicos , Humanos , Fenótipo , Recompensa , Transtornos Relacionados ao Uso de Substâncias/etnologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
17.
Zhonghua Xue Ye Xue Za Zhi ; 40(3): 195-199, 2019 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-30929385

RESUMO

Objective: To analyze the characteristics of myeloid neoplasms with t (3;21) (q26;q22) . Methods: Clinical data of patients with t (3; 21) (q26; q22) , diagnosed as hematologic malignancies in Peking University people's hospital from January 2011 to March 2018, were collected retrospectively. 19 patients in our hospital and forty-eight patients bearing t (3;21) (q26;q22) with detailed survival data reported in literature were summarized. Kaplan- Meier method was used for survival analysis. Results: Among 19 patients, including 15 males and 4 females with a median age of 36 years (22-68 years) , 4 cases was diagnosed as de novo acute myeloid leukemia (AML) , 4 as myelodysplastic syndromes (MDS) , 3 as MDS-AML and 8 as chronic myelogenous leukemia (CML) in myeloid blast transformation. All of the 19 patients were detected to have t (3;21) (q26;q22) by G-banding technique and 13 carried additional cytogenetic aberrations. 9 of the 19 patients were detected for positive AML1-MDS1 fusion genes. In the 9 patients with detailed follow-up data, 6 patients received chemotherapy and only 2 achieved complete remission (CR) while 4 with no response. During the follow-up period, 8 patients died and the median overall survival (OS) was 6 months (4.5 to 22 months) . Survival analysis of the present 9 patients together with the literature data showed that the prognosis was poor and the median OS was 7 months. In particular, AML/t-AML had the worst prognosis. Hematopoietic stem cell transplantation (HSCT) could significantly improve survival, the median OS in HSCT group and non-HSCT group were 20.9 and 4.7 months respectively (P<0.001) . Conclusions: t (3; 21) (q26; q22) is a rare recurrent chromosomal abnormality which is detected mainly in myeloid neoplasm and confer to poor clinical prognosis. HSCT should be recommended to improve the outcomes.


Assuntos
Leucemia Mieloide Aguda , Adulto , Idoso , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 3 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos , Estudos Retrospectivos , Translocação Genética , Adulto Jovem
18.
Int J Cancer ; 145(10): 2850-2860, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30977117

RESUMO

Lung metastasis is one of the leading causes of death for triple-negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole-genome sequencing and functional screening. Furthermore, we aimed to develop a metastasis-related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole-genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain-of-function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared to the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four-gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence-free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low- and high-risk subgroups of recurrence, helping frame personalized treatments for TNBC.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Animais , Linhagem Celular Tumoral , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Seguimentos , Mutação com Ganho de Função , Perfilação da Expressão Gênica , Biblioteca Gênica , Células HEK293 , Humanos , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Osteoprotegerina/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Prognóstico , Estudos Prospectivos , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Ophthalmology ; 126(10): 1445-1453, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31026493

RESUMO

PURPOSE: The Cancer Genome Atlas (TCGA) classification has been validated for uveal melanoma (UM) prognostication. We applied TCGA classification to UM biopsied using fine-needle aspiration biopsy (FNAB) to determine the predictability for metastasis and death. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with UM treated with plaque radiotherapy at Wills Eye Hospital, Philadelphia, Pennsylvania, from October 1, 2008, through December 31, 2018, who completed genetic analysis of chromosomes 3 and 8 after FNAB. METHODS: Tumors were classified as A, B, C, or D and were compared using the chi-square test, Fisher exact test, analysis of variance, and Kaplan-Meier analysis. MAIN OUTCOME MEASURES: Metastasis and death. RESULTS: Six hundred fifty-eight UM patients were categorized accordingly as TCGA class A (n = 342 [52%]), B (n = 91 [14%]), C (n = 118 [18%]), and D (n = 107 [16%]). More advanced tumor classification revealed older mean patient age (56 vs. 53 vs. 60 vs. 63 years, respectively; P < 0.001), worse presenting visual acuity (20/20-20/50: 81% vs. 67% vs. 71% vs. 66%, respectively; P < 0.001), greater distance from the optic disc (3.5 vs. 4.9 vs. 5.7 vs. 5.3 mm, respectively; P < 0.001), larger tumor basal diameter (10.3 vs. 12.9 vs. 13.9 vs. 15.3 mm, respectively; P < 0.001), and greater tumor thickness (4.3 vs. 6.1 vs. 6.6 vs. 7.5 mm, respectively; P < 0.001). After mean follow-up (47.6 vs. 47.6 vs. 42.9 vs. 28.7 months, respectively; P < 0.001), more advanced TCGA class was associated with increased risk of metastasis (3% vs. 10% vs. 25% vs. 41%, respectively; P < 0.001) and death (1% vs. 0% vs. 3% vs. 9%, respectively; P < 0.001). Compared with class A, the 5-year hazard ratio for metastasis increased at 4.1 (B vs. A; P = 0.01), 10.1 (C vs. A; P < 0.001), and 30.0 (D vs. A; P < 0.001). The 5-year hazard ratio for death increased at 3.1 (C vs. A; P = 0.11) and 13.7 (D vs. A; P < 0.001) with no deaths in class B. CONCLUSIONS: Grouping of UM using TCGA classification predicts the risk of melanoma-related metastasis and death.


Assuntos
Melanoma/genética , Neoplasias Uveais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/classificação , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Neoplasias Uveais/classificação
20.
Int J Cancer ; 145(10): 2670-2681, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30892690

RESUMO

High-grade serous epithelial ovarian cancer (HGS-EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS-EOC and their route toward malignancy. In our study, -omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS-EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region ß, 495 kb long). Analysis in two external databases confirmed regions α and ß are features of HGS-EOC. The MECOM gene is located in region α, and 15 genes are in region ß. No functional data are yet available for the genes in the ß region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS-EOC, opening up a potential biological role in its etiopathogenesis.


Assuntos
Carcinoma Epitelial do Ovário/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Neoplasias Ovarianas/genética , Biópsia , Carcinoma Epitelial do Ovário/patologia , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Feminino , Genômica , Humanos , Gradação de Tumores , Neoplasias Ovarianas/patologia , Ovário/patologia , Sequenciamento Completo do Exoma
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