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1.
Clin Biochem ; 73: 70-76, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31386834

RESUMO

BACKGROUND: Chromosomal region 9p21.3 is most robustly associated with coronary artery disease (CAD) in western European populations. However, heterogeneity in CAD phenotypes leads to uncertainty whether 9p21.3 is associated with stable and/or acute clinical presentations of CAD. 9p21.3 is rich in regulatory elements, but the underlying mechanisms of its actions in CAD remain unclear. We investigate the association of 9p21.3 two haplotype blocks lead variants (rs10757278 and rs518394) with first-ever non-fatal myocardial infarction (MI) in CAD patients and their association with CDKN2B mRNA expression in peripheral blood mononuclear cells 6 months after the event. METHODS: We included CAD patients with sustained first MI (n = 523) and controls (n = 583). Gene expression was assessed in 72 patients 6 months after MI and 43 healthy controls. TaqMan® technology was used for the gene expression and genotyping analysis. RESULTS: CDKN2B mRNA was significantly lower in MI patients compared with the controls (p = 0.002) and in patients carrying the rs10757278 G risk allele versus AA homozygotes (p = 0.012) 6 months after the event. While we confirmed the association of rs10757278 with CDKN2B expression in MI patients, we failed to find an association between the investigated variants and MI or disease burden. CONCLUSIONS: We suggest a dysregulation of gene expression in the 9p21.3 region six months after acute MI, which is affected by a genetic variant in patients. The rs10757278 rare allele is one factor that might lead to prolonged risk for proatherogenic complications.


Assuntos
Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Regulação da Expressão Gênica , Haplótipos , Infarto do Miocárdio , Elementos de Resposta , Adulto , Idoso , Alelos , Cromossomos Humanos Par 9/metabolismo , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Seguimentos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 837-840, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400141

RESUMO

OBJECTIVE: To analyze the clinical and molecular genetic characteristics of patient with Kleefstra syndrome 1. METHODS: Clinical data, chromosomal karyotype and whole genome copy number variations (CNVs) of the patient were analyzed. RESULTS: The patient was found to have a karyotype of 45,XX,-9[4]/46,XX,r(9)(p24q34)[56]. Whole-genome CNVs detection revealed that she has carried a heterozygous deletion of approximately 670 kb at 9q34.3, which encompassed the entire EHMT1 gene. The region is strongly associated with Kleefstra syndrome (1/9q telomere deletion). In addition, the patient also had heterozygous deletion of 9pter, which may predispose to formation of ring chromosome 9. CONCLUSION: The child was diagnosed with Kleefstra syndrome type 1 in conjunct with ring chromosome 9.


Assuntos
Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Cromossomos em Anel , Criança , Deleção Cromossômica , Variações do Número de Cópias de DNA , Feminino , Humanos
3.
Cytogenet Genome Res ; 158(2): 74-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141803

RESUMO

Deletion of distal 9p is associated with a rare clinical condition characterized by dysmorphic features, developmental delay, and ambiguous genitalia. The phenotype shows variable expressivity and is related to the size of the deletion. 8q24 duplication has been reported in only few cases to date, all showing dysmorphic features and mild psychomotor developmental delay. A case of chromosomal aberration involving a 9p terminal deletion with an 8q duplication has never been reported. Here, we describe a child with a female phenotype, male karyotype, dysmorphic features, ambiguous genitalia, and developmental delay. In order to assess the cause of the patient's phenotype, conventional karyotyping, FISH, and a chromosomal microarray analysis were performed on the patient and her parents. The cytogenetic and molecular analysis revealed an unbalanced chromosomal aberration with a duplication in the long arm of chromosome 8 at 8q24.11q24.3 associated with a distal deletion in the short arm of chromosome 9 at 9p24.3p24.1, derived from a maternal balanced translocation. We compared the clinical picture of our patient with other similar cases reported in the literature and found that some clinical findings, such as strabismus, symphalangism of the first finger, and cubitus valgus, have never been previously associated with 9p deletion or 8q duplication expanding the phenotypic range of this condition. This study is aimed to better define the clinical history and prognosis of patients with this rare chromosomal aberration.


Assuntos
Cromossomos Humanos Par 9/genética , Deficiências do Desenvolvimento/genética , Disgenesia Gonadal 46 XY/genética , Trissomia/genética , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 8/genética , Feminino , Humanos
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(4): 336-339, 2019 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-30950020

RESUMO

OBJECTIVE: To determine the nature and origin of aberrant chromosomes in a child with multiple anomalies and psychomotor retardation. METHODS: Routine G-banding was carried out to analyze the karyotypes of the patient and his parents, and next generation sequencing for copy number variations (CNV-seq) was used for the fine mapping of the aberrant chromosomal regions. RESULTS: The proband and his uncle exhibited psychomotor retardation, craniofacial malformation, infantile external genitalia, and concealed penis. Cytogenetic analysis indicated that the child has a 46,XYqh+,+(9),t(9;13)(q13;q12),pat,-13 karyotype. His uncle was XYqh+,+(9),t(9;13)(q13;q12)mat,-13, his father was 46,XYqh+,t(9;13)(q13;q12)mat, his grandmother was 46,XX,t(9;13)(q13;q12), and his grandfather was 46,XYqh+. The result of CNV-seq assay for the child was 46,XY,+9p(pter-p13.2,-40 Mb×3). No deletion was detected. CONCLUSION: The partial trisomy 9 and partial monosomy 13 probably underlie the phenotypic abnormalities in the child. Combined chromosomal karyotyping and DNA sequencing can facilitate delineation of the nature and origin of the aberrant chromosomes.


Assuntos
Anormalidades Múltiplas , Trissomia , Criança , Deleção Cromossômica , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 9 , Variações do Número de Cópias de DNA , Humanos , Cariotipagem , Masculino , Monossomia , Linhagem , Translocação Genética
5.
Cytogenet Genome Res ; 157(4): 231-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933949

RESUMO

Constitutional complex chromosomal rearrangements (CCRs) are rare events that typically involve 2 or more chromosomes with at least 3 breakpoints and can result in normal or abnormal phenotypes depending on whether they disturb the euchromatic neighborhood. Here, we report an unusual balanced CCR involving chromosomes 1, 9, and 10 that causes an unbalanced karyotype in a severely affected toddler. The CCR was initially reported as a maternal 2-way translocation but was reclassified as a 3-way translocation after a microarray analysis of the propositus revealed the involvement of another chromosome not identified by G-banding in his phenotypically normal mother. FISH assays on maternal metaphase cells confirmed that the 1qter region of der(1) was translocated to der(10), whereas the 10qter segment was translocated to der(9), which in turn donated a segment to der(1). Subsequently, this CCR was also identified in her phenotypically normal father (the patient's grandfather). Thus, the patient inherited the previously unreported pathogenic combination of der(1) with a loss of 1q43→qter (including AKT3, ZBTB18, HNRNPU, and SMYD3) and der(9) with a gain of 10q25.2→qter (including FGFR2), leading to a compound phenotype with key features of the 1q43→qter deletion and distal 10q trisomy syndromes. Our observations suggest that the loss of SMYD3 accounts for cardiac defects in a subset of patients. Moreover, due to recurrent miscarriages in this family, our findings allowed improved genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 9/genética , Anormalidades Múltiplas/diagnóstico por imagem , Pré-Escolar , Hibridização Genômica Comparativa , Aconselhamento Genético , Histona-Lisina N-Metiltransferase/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Tomografia Computadorizada por Raios X , Translocação Genética
6.
Leukemia ; 33(8): 1895-1909, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30842609

RESUMO

Chromosomal rearrangements and specific aneuploidy patterns are initiating events and define subgroups in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here we analyzed 250 BCP-ALL cases and identified a novel subgroup ('PAX5-plus', n = 19) by distinct DNA methylation and gene expression profiles. All patients in this subgroup harbored mutations in the B-lineage transcription factor PAX5, with p.P80R as hotspot. Mutations either affected two independent codons, consistent with compound heterozygosity, or suffered LOH predominantly through chromosome 9p aberrations. These biallelic events resulted in disruption of PAX5 transcriptional programs regulating B-cell differentiation and tumor suppressor functions. Homozygous CDKN2A/B deletions and RAS-activating hotspot mutations were highly enriched as cooperating events in the genomic profile of PAX5-plus ALL. Together, this defined a specific pattern of triple alterations, exclusive to the novel subgroup. PAX5-plus ALL was observed in pediatric and adult patients. Although restricted by the limited sample size, a tendency for more favorable clinical outcome was observed, with 10 of 12 adult PAX5-plus patients achieving long-term survival. PAX5-plus represents the first BCP-ALL subgroup defined by sequence alterations in contrast to gross chromosomal events and exemplifies how deregulated differentiation (PAX5), impaired cell cycle control (CDKN2A/B) and sustained proliferative signaling (RAS) cooperatively drive leukemogenesis.


Assuntos
Mutação , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Cromossomos Humanos Par 9 , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Metabolismo Energético , Humanos , Perda de Heterozigosidade
8.
Cancer Genet ; 231-232: 1-13, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803551

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is not as frequently reported as the B-cell counterpart (B-ALL), only occurring in about 15% of pediatric cases with a typically heterogeneous etiology. Approximately 8% of childhood T-ALL cases have rearrangements involving the ABL1 tyrosine kinase gene at 9q34.12; although a t(9;22), resulting in a fusion of ABL1 with the BCR gene at 22q11.23 is a common occurrence in B-ALL, it is not a typical finding in T-ALL. A subset of 10 of 40 documented cases of T-ALL analyzed over a 5-year period is presented, each having gene rearrangements within band 9q34 that resulted in fusions other than BCR/ABL1. These cases included fusions involving ABL1, SET (9q34.11), NUP214 (9q34.13), SPTAN1 (9p34.11), and TNRC6B (22q13.1). Among the 10 cases are: six SET/NUP214 fusions, two ABL1/NUP214 fusions (one of which was associated with episomal amplification) and novel SPTAN1/ABL1 and TNRC6B/ABL1 fusions. The evaluations of these clones were each significantly aided by FISH analysis, which directed subsequent microarray and anchored multiplex PCR testing for fusion confirmations.


Assuntos
Cromossomos Humanos Par 9/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Criança , Pré-Escolar , Humanos
9.
Acta pediatr. esp ; 77(1/2): e31-e34, ene.-feb. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-182878

RESUMO

El síndrome de Kleefstra se caracteriza por una facies peculiar y la presencia de hipotonía, déficit intelectual y retraso grave en la expresión oral, aunque pueden aparecer otras anomalías: cardiacas, de audición, defectos genitales en varones, epilepsia, infecciones respiratorias severas, sobrepeso y alteraciones del comportamiento. Se trata de una enfermedad genética poco frecuente, ocasionada por mutaciones puntuales en el gen histona-lisina-N-metiltransferasa 1 eucromática (EHMT1) o por una microdeleción cromosómica en 9q34.3 (en el 75% de los casos). Este gen codifica una enzima que modifica la función de la histona, esencial para el desarrollo normal. Presentamos el caso clínico de un niño con hipotonía, retraso psicomotor, ausencia de habla y facies peculiar, cuyo diagnóstico se obtuvo gracias a las nuevas técnicas de genética molecular


The Kleefstra syndrome is characterized by a peculiar facies, intelectual deficit and severe delay in the oral expression. Other anomalies that may occur are cardiac, hearing, genital defects in men, epilepsy, severe respiratory infections, overweight and behavioral abnormalities. It’s a rare genetic disorder caused by mutations in the eucromatic histone-lysine-N-methyltransferase 1 (EHMT1) or a chromosome microdeletion 9q34.3 (in 75% of the cases). This gene encodes an enzyme that modifies the function of histone, essential for normal development. We present the case of a child with hypotonia, psychomotor retardation, absence of speech and peculiar facies, whose diagnosis was obtained due to the new techniques in molecular genetics


Assuntos
Humanos , Masculino , Pré-Escolar , Cromossomos Humanos Par 9/genética , Deleção Cromossômica , Deficiência Intelectual/genética , Anormalidades Craniofaciais/genética , Síndrome
10.
Cell Stem Cell ; 24(2): 203-205, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30735646

RESUMO

Genome-wide association studies (GWASs) have robustly found a correlation between coronary artery disease (CAD) and an intergenic region at locus 9p21.3. However, the mechanistic implication of this association is unknown. Recently in Cell, Lo Sardo et al. used hiPSC genome editing to demonstrate how this locus contributes to CAD predisposition.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Cromossomos Humanos Par 9 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
J Assist Reprod Genet ; 36(4): 769-775, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30675680

RESUMO

PURPOSE: Male carriers of an X-autosome translocation are generally infertile, regardless of the position of the breakpoint on the X chromosome while the pathogenicity of Xp22.3 subtelomeric duplications is under debate. To shed light into this controversy, we present a rare case, of an azoospermic male with no other significant clinical findings, in whom classical cytogenetics revealed additional unbalanced chromosomal material, at the telomere of the long arm of one homolog of chromosome 9. METHODS: In peripheral blood specimens of the index case and his parents, we performed GBanding, Inverted-DAPI Banding, AgNOR staining, Telomere specific Fluorescence in Situ Hybridization (FISH), Molecular karyotyping by Multi-color FISH, whole genome SNP microarrays, sub-telomeric MLPA, and transcription analysis of the expression of KAL1 gene by RT-PCR. RESULTS: Multi-color FISH revealed an unbalanced translocation involving the short arm of chromosome X. SNP microarray analysis combined to classical cytogenetics and MLPA demonstrated a de novo 8.796 Mb duplication of Xp22.31-p22.33. Compared to three control specimens, the patient presented significantly elevated expression levels of KAL1 mRNA in peripheral blood, suggesting transcriptional functionality of the duplicated segment. CONCLUSIONS: The duplicated segment contains the pseudo-autosomal region PAR1 and more than 30 genes including SHOX, ARSE, STS, KAL1, and FAM9A and is not listed as polymorphic. Our data advocate that duplications of the Xp22.3 region may not be associated with a clinical consequence.


Assuntos
Cromossomos Humanos Par 9/genética , Cromossomos Humanos X/genética , Infertilidade Masculina/genética , Translocação Genética/genética , Adulto , Criança , Bandeamento Cromossômico/métodos , Duplicação Cromossômica/genética , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Infertilidade Masculina/patologia , Cariotipagem , Masculino , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Telômero/genética
13.
Nat Commun ; 10(1): 368, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664630

RESUMO

The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC.


Assuntos
Carcinoma de Células Acinares/genética , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Neoplasias das Glândulas Salivares/genética , Proteínas e Peptídeos Salivares/genética , Translocação Genética , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Carcinoma de Células Acinares/metabolismo , Carcinoma de Células Acinares/patologia , Proliferação de Células , Cromatina/química , Cromatina/metabolismo , Cromossomos Humanos Par 4/química , Cromossomos Humanos Par 4/metabolismo , Cromossomos Humanos Par 9/química , Cromossomos Humanos Par 9/metabolismo , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Feminino , Loci Gênicos , Humanos , Masculino , Camundongos , Família Multigênica , Cultura Primária de Células , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Proteínas e Peptídeos Salivares/metabolismo
14.
Mol Carcinog ; 58(5): 760-766, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30604909

RESUMO

9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10-4 ). In conclusion, our study provided evidence that rs1537373 in ANRIL may influence transcription factor binding and regulate CDKN2B expression, thus confer the susceptibility to PC.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 9 , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
15.
J Forensic Leg Med ; 61: 92-96, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528850

RESUMO

A 5-year-old boy with a chromosome-9 abnormality and multiple external and visceral malformations was found in cardiopulmonary arrest during a regular visit to the hospital; he did not respond to cardiopulmonary resuscitation and died. An odontoid process fracture and calcification and fibrosis of the muscles around the superior cervical vertebra were observed during the autopsy. Postmortem computed tomography revealed an anterior dislocation of the atlas; odontoid synchondrosis fracture; and delayed, incomplete bony fusion of the odontoid process relative to his age. The cause of his death was a superior spinal cord injury. The tissue surrounding the upper cervical spine presented with myositis ossificans, suggesting a prior injury. He experienced a minor traffic accident 3 months before his death. It was concluded that the odontoid synchondrosis fracture occurred during the accident based on the incomplete bony fusion and atlantoaxial instability, which were consistent with the findings of myositis ossificans. Delayed fatal dislocation may then have occurred under the influence of a minor external force. Odontoid process abnormalities and atlantoaxial instability are common in patients with trisomy 21 and other congenital diseases; however, the condition's association with chromosome-9 abnormalities has not been reported. In children with various chromosomal abnormalities, periodic assessment of instability and morphology of the cervical spine, and a lowered examination threshold for the children at risk, could prove useful in the prevention injuries leading to fatality, and provide additional information to rule out abuse.


Assuntos
Articulação Atlantoaxial/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 9 , Luxações Articulares/patologia , Processo Odontoide/lesões , Fraturas da Coluna Vertebral/patologia , Pré-Escolar , Evolução Fatal , Parada Cardíaca/etiologia , Humanos , Masculino , Miosite Ossificante/patologia
16.
Cell ; 175(7): 1796-1810.e20, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30528432

RESUMO

The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for ∼10%-15% of disease in non-African populations. The ∼60 kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Here, we produce induced pluripotent stem cells (iPSCs) from risk and non-risk individuals, delete each haplotype using genome editing, and generate vascular smooth muscle cells (VSMCs). Risk VSMCs exhibit globally altered transcriptional networks that intersect with previously identified CAD risk genes and pathways, concomitant with aberrant adhesion, contraction, and proliferation. Unexpectedly, deleting the risk haplotype rescues VSMC stability, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This study shows that the risk haplotype selectively predisposes VSMCs to adopt a cell state associated with CAD phenotypes, defines new VSMC-based networks of CAD risk genes, and establishes haplotype-edited iPSCs as powerful tools for functionally annotating the human genome.


Assuntos
Cromossomos Humanos Par 9 , Doença da Artéria Coronariana , Edição de Genes , Haplótipos , Células-Tronco Pluripotentes Induzidas , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 9/genética , Cromossomos Humanos Par 9/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Feminino , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transcrição Genética
17.
Hum Pathol ; 82: 39-45, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30539796

RESUMO

Undifferentiated malignancies (UMs) encompass a diverse set of aggressive tumors that pose not only a diagnostic challenge but also a challenge for clinical management. Most tumors in this category are currently treated empirically with nonspecific chemotherapeutic agents that yield extremely poor clinical response. Given that UMs are inherently genetically unstable neoplasms with the potential for immune dysregulation and increased neoantigen production, they are likely to be particularly amenable to immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2, to promote T-cell antitumor activity. Aberrant expression of PD-L1 and, more recently, chromosomal 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations can be used as biomarkers to predict responsiveness to checkpoint inhibitors. Here we evaluated 93 cases previously diagnosed as an "undifferentiated" malignancy and found that 56% (52/93) of UMs moderately to strongly express PD-L1 by immunohistochemistry (IHC). Concurrent CD274(PD-L1) and PDCD1LG2(PD-L2) fluorescence in situ hybridization (FISH) was performed on 24 of these cases and demonstrates a genetic gain at both loci in 62.5% of UMs. Genetic alterations at the CD274(PD-L1) and PDCD1LG2(PD-L2) loci were found to be completely concordant by FISH. Overall, we found that a significant proportion of UMs express PD-L1 and provide molecular support for using checkpoint inhibitors as a treatment approach for this class of tumors.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Diferenciação Celular , Imunoterapia/métodos , Neoplasias/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 9 , Bases de Dados Factuais , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Proteína 2 Ligante de Morte Celular Programada 1/genética , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
18.
BMC Cancer ; 18(1): 1259, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558563

RESUMO

BACKGROUND: Genetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity. This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance. METHODS: Sanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 for the detection of 9p21 alterations. Expression levels of the CDKN2A and MTAP by real-time PCR were evaluated in cases with 9p21 deletions. Statistical analysis of genetic and clinical data was performed using Graph Pad Prism 5 and SPSS Statistics 24 software. RESULTS: In our cohort it was observed that 7 /78 (8,9%) of the low-grade tumors recurred and 2 (2,6%) showed malignant transformation. BRAF V600E mutations were detected in 15 cases. No statistically significant correlations were found between the presence of BRAF V600E mutation and patient's morphologic or clinical features. Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p = 0.0178) but frequent in grade IV gliomas (62.5%, p = 0.0087). Moreover it was found that deletions at these loci were correlated with a shorter overall survival (p = 0.011) and a shorter progression-free survival (p = 0.016). CONCLUSIONS: It was demonstrated that in these tumors BRAF V600E mutated and that CDKN2A/B MTAP co-deletions may be used for stratifying patients for a stricter surveillance. The Investigating and defining if glial tumors with CDKN2A/B and MTAP homozygous loss may be vulnerable to new forms of therapy, namely those affecting the methionine salvage pathway, was proven to be of importance.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 9/genética , Glioma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Deleção de Genes , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Fosforilases/genética , Análise de Sequência de DNA
19.
Medicine (Baltimore) ; 97(42): e12875, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335005

RESUMO

RATIONALE: Variant Philadelphia chromosome translocations involving chromosomes other than chromosomes 9 and 22 have been reported in 5% to 10% of patients with chronic myeloid leukemia (CML). Here, a case of CML with a t (9, 22, 16) (q34; q11; p13) translocation, which has never been described, is reported. PATIENT CONCERNS: A 59-year-old female with dry cough, referred to our hospital, exhibited hepatosplenomegaly, high basophil count, and high platelet count at admission without any other known chronic diseases. DIAGNOSES: The patient was diagnosed with CML with the translocation t (9;22;16) (q34; q11; p13). The patient was treated with imatinib, a first-generation tyrosine kinase inhibitor (TKI), discontinuously, achieving a complete hematological response for 7 years. Since November 8, 2017, the patient had recurrent fever, and her platelet count rose to 1422 × 10/L. Subsequently, the E279K mutation in the BCR-ABL kinase region was detected. OUTCOMES: According to a previous report, this mutation confers sensitivity to nilotinib, a second-generation TKI. In the end, the patient received treatment with nilotinib and showed a complete hematological response. LESSONS: The present study reports a rare case of CML with Ph chromosome and a t (9;22;16) (q34; q11; p13) translocation. For such cases about CML with variant Philadelphia chromosome translocations or BCR-ABL kinase region mutation, TKI may still be valuable.


Assuntos
Antineoplásicos/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Pirimidinas/administração & dosagem , Translocação Genética/genética , Cromossomos Humanos 16-18/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Cromossomo Filadélfia
20.
J Environ Pathol Toxicol Oncol ; 37(2): 117-126, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30055547

RESUMO

Elucidation of cryptic BCR/ABL1 gene rearrangement is exceptionally important in the clinical diagnosis and prognosis of chronic myelogenous leukemia (CML). Previous reports indicated an adverse prognostic effect of atypical BCR/ABL1 gene rearrangements with submicroscopic ABL1-BCR deletions on derivative chromosome 9 [der(9)] in CML patients. Dual color dual fusion locus-specific BCR/ABL1 fluorescent in situ hybridization (FISH) analysis together with G-banding using trypsin and Giemsa (GTG banding) was performed in 489 patients at different stages of CML to investigate the spectrum of BCR/ABL1 gene rearrangements. Among the study group analyzed, a significantly higher frequency of BCR/ABL1 gene rearrangements that is consistent with der(9) deletion were observed in the blast crisis (BC) phase at 41.67%, followed by the accelerated phase (AP) at 36.84%, the imatinib mesylate (IM)-resistant chronic phase (CP) at 23.08%, and the lowest incidence was found in de novo CP at 16.61%. 1R1G1F (1 red, 1 green, 1 fusion) with concurrent loss of ABL1-BCR fusion gene on der(9) chromosome was the major signal pattern identified in each group. The results from the current study show that this unusual BCR/ABL1 gene rearrangement is one of the steering forces toward disease progression in CML. Patients in AP/BC of CML with der(9) deletion showed poor response to IM therapy; however, patients with der(9) deletion in the early phases of CML responded well to IM treatment. Therefore, the establishment of an atypical FISH signal pattern in CML is of paramount important because it is associated with adverse clinical prognostic implications in advanced stages of the disease.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Rearranjo Gênico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
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