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1.
Genes (Basel) ; 12(5)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925474

RESUMO

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.


Assuntos
Cromossomos Humanos Par 8/genética , Deleção de Sequência/genética , Adolescente , Adulto , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Deleção Cromossômica , Disfunção Cognitiva/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Fenótipo
2.
Nature ; 593(7857): 101-107, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33828295

RESUMO

The complete assembly of each human chromosome is essential for understanding human biology and evolution1,2. Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the ß-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence.


Assuntos
Cromossomos Humanos Par 8/química , Cromossomos Humanos Par 8/genética , Evolução Molecular , Animais , Linhagem Celular , Centrômero/química , Centrômero/genética , Centrômero/metabolismo , Cromossomos Humanos Par 8/fisiologia , Metilação de DNA , DNA Satélite/genética , Epigênese Genética , Feminino , Humanos , Macaca mulatta/genética , Masculino , Repetições Minissatélites/genética , Pan troglodytes/genética , Filogenia , Pongo abelii/genética , Telômero/química , Telômero/genética , Telômero/metabolismo
3.
Genes Dev ; 35(7-8): 556-572, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766983

RESUMO

Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1-induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.


Assuntos
Carcinogênese/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Sarcoma de Ewing/genética , Estresse Fisiológico/genética , Trissomia/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Cromossomos Humanos Par 8/genética , Replicação do DNA/genética , Proteínas de Ligação a DNA/genética , Duplicação Gênica/genética , Regulação Neoplásica da Expressão Gênica , Humanos
4.
Am J Med Genet A ; 185(5): 1461-1467, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33619900

RESUMO

Diagnosis of rare copy number variants (CNVs) with scarce literature evidence poses a major challenge for interpretation of the clinical significance of chromosomal microarray analysis (CMA) results, especially in the prenatal setting. Bioinformatic tools can be used to assist in this issue; however, this prediction can be imprecise. Our objective was to describe the phenotype of the rare copy number losses encompassing the 8q24.13-q24.3 locus, and to find common features in terms of genomic coordinates, gene content, and clinical phenotypic characteristics. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature and public databases search was performed. Local database search yielded seven new patients with del (8)(q24.13q24.3) (one of these with an additional copy number variant). Literature and public databases search yielded eight additional patients. The cases showed high phenotypic variability, ranging from asymptomatic adults and fetuses with normal ultrasound to patients with autism/developmental delay (6/11 postnatal cases, 54.5%). No clear association was noted between the specific disease-causing/high-pLI gene content of the described del (8)(q24.13q24.3) to neurodevelopmental disorders, except for a possibly relevant locus encompassing the KCNQ3 gene. We present the challenges in classification of rare variants with limited clinical information. In such cases, genotype-phenotype correlation must be assessed with extra-caution and possibly using additional methods to assist the classification, especially in the prenatal setting.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Deficiências do Desenvolvimento/genética , Transtornos do Neurodesenvolvimento/genética , Adulto , Criança , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Masculino , Análise em Microsséries/economia , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Gravidez
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(2): 145-149, 2021 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-33565068

RESUMO

OBJECTIVE: To explore the genetic etiology for a newborn with corneal opacity. METHODS: The neonate and her parents were subjected to routine G-banding chromosomal karyotyping analysis. Copy number variation (CNV) was analyzed with low-coverage whole-genome sequencing (WGS) and single nucleotide polymorphism microarray (SNP array). RESULTS: No karyotypic abnormality was found in the newborn and her parents. Low-coverage WGS has identified a de novo 5.5 Mb microdeletion at chromosome 8q21.11-q21.13 in the neonate, which encompassed the ZFHX4 and PEX2 genes. The result was confirmed by SNP array-based CNV analysis. CONCLUSION: The newborn was diagnosed with chromosome 8q21.11 deletion syndrome. ZFHX4 may be one of the key genes underlying this syndrome.


Assuntos
Variações do Número de Cópias de DNA , Testes Genéticos , Monossomia/genética , Bandeamento Cromossômico , Cromossomos Humanos Par 8/genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Recém-Nascido , Cariotipagem , Fator 2 da Biogênese de Peroxissomos/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
6.
Stem Cell Res ; 52: 102226, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33588214

RESUMO

Cases in which the duplication of chromosome 8p (dup 8p) is observed are characterized by facial dysmorphism, agenesis/hypoplasia of the corpus callosum, heart defects and severe mental retardation. The frequency of dup 8p cases is higher compared to other chromosomes because of the Non-allelic homologous recombination (NAHR) between two segmental duplication regions (SDs) containing olfactory receptor gene clusters, REPD (repeat-distal) and REPP (repeat-proximal), located in chromosome 8p23.1. Here we generated a human iPSC line from a patient's amniotic fluid cells with a 18 Mb duplication in 8p23.3p22, which will serve as useful tools for studying dup 8p syndrome.


Assuntos
Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual , Líquido Amniótico , Cromossomos , Cromossomos Humanos Par 8/genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética
7.
Cancer Res ; 81(8): 1925-1936, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33472888

RESUMO

MYC is embedded in the transcriptional oasis of the 8q24 gene desert. A plethora of genomic elements has roles in MYC aberrant expression in cancer development by interacting with transcription factors and epigenetics regulators as well as altering the structure of chromatin at the MYC locus and tissue-specific long-range enhancer-promoter contacts. Furthermore, MYC is a master regulator of several human cancers by modulating the transcription of numerous cancer-related genes through epigenetic mechanisms. This review provides a comprehensive overview of the three-dimensional genomic organization around MYC and the role of epigenetic machinery in transcription and function of MYC as well as discusses various epigenetic-targeted therapeutic strategies in MYC-driven cancers.


Assuntos
Cromatina/ultraestrutura , Epigênese Genética/fisiologia , Regulação Neoplásica da Expressão Gênica , Genes myc/fisiologia , Neoplasias/genética , Fatores de Transcrição/fisiologia , Fator de Ligação a CCCTC , Cromossomos Humanos Par 8/genética , Progressão da Doença , Genes Neoplásicos , Sequências Hélice-Alça-Hélice , Humanos , MicroRNAs/fisiologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/fisiologia , Elementos Reguladores de Transcrição
8.
Hematol Oncol ; 39(1): 66-74, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32979280

RESUMO

The prognosis of diffuse large B-cell lymphoma (DLBCL) having MYC rearrangement (MYC-R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC-R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC-R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21-67) years. Twenty-six (54%) patients had MYC-R only (single hit), and 22 (46%) had MYC-R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto-SCT during the first complete response (CR), both the 2-year overall survival (OS) and progression-free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%-91.2%). In 20 patients who received auto-SCT after relapsed or refractory state, the 2-year OS and PFS rates were 68.2% (95% CI, 41.9%-84.5%) and 59.6% (95% CI, 35.1%-77.4%), respectively. In 17 patients who received allo-SCT, only 4 patients underwent SCT in CR. The 2-year OS and PFS rates were 29.4% (95% CI, 10.7%-51.1%) and 17.6% (95% CI, 4.3%-38.3%), respectively. The rate of non-relapse mortality at 1 year was 41.2% (95% CI, 17.1%-64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto-SCT may be effective for MYC-R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo-SCT not in CR, the outcome of allo-SCT was unsatisfactory due to high non-relapse mortality and early relapse. To clarify the role of allo-SCT for MYC-R DLBCL, further accumulation of patients is necessary.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
10.
Eur J Med Genet ; 64(1): 104118, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33248287

RESUMO

We described a new second case of fetoplacental discrepancy involving first trimester prenatal detection of mosaic isochromosome i (8) (q10). A 32-year-old woman underwent chorionic villous sampling because of increased fetal nuchal translucency. Analysis of direct chromosome preparations was performed by R-banding and FISH using subtelomeric, centromeric and whole chromosome painting probes for chromosome 8 showing the presence of an isochromosome 8q with a complex, female mosaic karyotype: mos 46,XX,i (8) (q10)[13]/46,XX,del (8) (p23)[10]. Cytogenetic analysis of cultured CVS showed an interstitial duplication with concomitant terminal deletion of the short arm of chromosome 8: 46,XX,der (8)del (8) (p23)dup (8) (p?)[18]. Array-CGH analysis from cultured trophoblasts and fetal tissues revealed a 6.69 Mb terminal deletion in 8p23.3p23.1 associated with a 31.49 Mb duplication in 8p23.1p11.1. FISH analysis confirmed the 8p inverted duplication deletion syndrome. Moreover, polymorphic DNA marker analysis demonstrated that the derivative chromosome 8 was of maternal origin. FISH analysis of cultured peripheral blood lymphocytes showed that the mother also carried a cryptic paracentric inversion inv (8) (p23). Our report contributes to expand the fetal phenotype of 8p inverted duplication deletion syndrome and also provides further insight into the underlying mechanism of this rare genomic disorder.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 8/genética , Mosaicismo , Fenótipo , Adulto , Transtornos Cromossômicos/patologia , Inversão Cromossômica , Feminino , Feto/anormalidades , Feto/diagnóstico por imagem , Humanos , Medição da Translucência Nucal , Gravidez
11.
Life Sci ; 264: 118729, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166592

RESUMO

Copy number alterations are widespread in cancer genomes and are part of the genomic instability underlying the pathogenesis of neoplastic diseases. Recurrent copy number alterations of specific chromosomal loci may result in gains of oncogenes or losses of tumor suppressor genes and become entrenched in the genomic framework of certain types of cancers. The locus at chromosome 8p11.23 presents recurrent amplifications most commonly in squamous lung carcinomas, breast cancers, squamous esophageal carcinomas, and urothelial carcinomas. Amplification is rare in other cancers. The amplified segment involves several described oncogenes that may promote cancer cell survival and proliferation, as well as less well characterized genes that could also contribute to neoplastic processes. Genes proposed to be "drivers" in 8p11.23 amplifications include ZNF703, FGFR1 and PLPP5. Additional genes in the locus that could be functionally important in neoplastic networks include co-chaperone BAG4, lysine methyltransferase NSD3, ASH2L, a member of another methyltransferase complex, MLL and the mRNA processing and translation regulators LSM1 and EIF4EBP1. In this paper, genes located in the amplified segment of 8p11.23 will be examined for their role in cancer and data arguing for their importance for cancers with the amplification will be presented.


Assuntos
Cromossomos Humanos Par 8/genética , Amplificação de Genes , Neoplasias/genética , Humanos
12.
Cancer Med ; 10(3): 1091-1102, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33382538

RESUMO

High-dose cytarabine (Ara-C) has been reported with increased treatment-related mortality, whereas few data are available concerning intermediate-dose Ara-C for induction of acute myeloid leukemia (AML) with t(8;21) translocation. We retrospectively analyzed factors impacting complete remission (CR), event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS) in 197 adults with t(8;21) AML, of whom 107 cases were induced with intermediate-dose and 90 with standard-dose Ara-C (as part of 3 + 7 protocol). After a single induction course, the overall CR rate was 87.6% (170/194), with a significant difference between the standard-dose (83/105, 79.0%) and intermediate-dose (87/89, 97.8%) groups (p < 0.001). Rather than general KITmut, the specific KIT-D816 independently led to a lower probability of achieving CR (HR = 3.29 [1.18-9.24], p = 0.023), worse EFS (HR = 3.53 [1.82-6.84], p < 0.001), and OS (HR = 5.45 [1.77-16.84], p = 0.003) in the standard-dose group, but not in the intermediate-dose group. CD19(+) represented the only independent factor predicting lower CIR both in the standard-dose group (HR = 0.32 [0.10-1.00], p = 0.050) and in the intermediate-dose group (HR = 0.11 [0.03-0.40], p = 0.001). When combined, KIT(+) plus CD19(-) conferred the most increased relapse risk (3-year CIR 60%; SE 0.12). Specific KIT-D816, instead of general KITmut, may be incorporated in prognostication model for t(8;21) AML. Combination of CD19 with KIT provides a more definite risk stratification profile for t(8;21) AML.


Assuntos
Antígenos CD19/metabolismo , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Translocação Genética , Adolescente , Adulto , Idoso , Antígenos CD19/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/análise , China/epidemiologia , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Adulto Jovem
13.
Gene ; 773: 145363, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33338509

RESUMO

Acute myelogenous leukemia (AML) is one of the major hematological malignancies. In the human genome, several have been found to originate from retroviruses, and some of which are involved in the progression of various cancers. Hence, to investigate whether retroviral-like genes are associated with AML development, we conducted a transcriptome sequencing analysis of 12 retroviral-like genes of 150 AML patients and 32 healthy donor samples, of which RNA sequencing data were obtained from public databases. We found high expression of ERV3-1, an envelope gene of endogenous retrovirus group 3 member 1, in all AML patients examined in this study. In particular, blood and bone marrow cells of the myeloid lineage in AML patients, exhibited higher expression of ERV3-1 than those of the monocytic AML lineage. We also examined the protein expression of ERV3-1 by immunohistochemical analysis and found expression of the ERV3-1 protein in all 12 myeloid-phenotype patients and 7 out of 12 monocytic-phenotype patients, with a particular concentration observed at the membrane of some leukemic cells. Transcriptome analysis further suggested that upregulated ERV3-1 expression may be associated with chromosome 8 trisomy as anomaly was found to be more common among the high expression group than the low expression group. However, this finding was not corroborated by the immunohistochemical data. This discrepancy may have been caused, in part, by the small number of samples analyzed in this study. Although the precise associated molecular mechanisms remain unclear, our results suggest that ERV3-1 may be involved in AML development.


Assuntos
Produtos do Gene env/genética , Leucemia Mieloide Aguda/genética , Leucócitos/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem da Célula , Cromossomos Humanos Par 8/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Leucócitos/virologia , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Retroviridae/genética , Trissomia/genética , Trissomia/patologia
14.
Braz J Med Biol Res ; 54(2): e9549, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33263645

RESUMO

Single nucleotide polymorphisms (SNPs) have important application value in the research of population genetics, hereditary diseases, tumors, and drug development. Conventional methods for detecting SNPs are typically based on PCR or DNA sequencing, which is time-consuming, costly, and requires complex instrumentation. In this study, we present a duplex probe-directed recombinase amplification (duplex-PDRA) assay that can perform real-time detection of two SNPs (rs6983267 and rs1447295) in four reactions in two tubes at 39°C within 30 min. The sensitivity of duplex-PDRA was 2×103-104 copies per reaction and no cross-reactivity was observed. A total of 382 clinical samples (179 prostate cancer patients and 203 controls) from northern China were collected and tested by duplex-PDRA assay and direct sequencing. The genotyping results were completely identical. In addition, the association analysis of two SNPs with prostate cancer risk and bone metastasis was conducted. We found that the TT genotype of rs6983267 (OR: 0.42; 95%CI: 0.23-0.78; P=0.005) decreased the risk of prostate cancer, while the CA genotype of rs1447295 (OR: 1.89; 95%CI: 1.20-2.96; P=0.005) increased the risk of prostate cancer. However, no association between the two SNPs (rs6983267 and rs1447295) and bone metastasis in prostate cancer was found in this study (P>0.05). In conclusion, the duplex-PDRA assay is an effective method for the simultaneous detection of two SNPs and shows great potential for widespread use in research and clinical settings.


Assuntos
Cromossomos Humanos Par 8/genética , Análise Mutacional de DNA/métodos , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata , Estudos de Casos e Controles , China , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Neoplasias da Próstata/genética , Recombinases
15.
Genes (Basel) ; 11(12)2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33316910

RESUMO

Ring chromosome 8 (r(8)) is one of the least frequent ring chromosomes. Usually, maternal chromosome 8 forms a ring, which can be lost from cells due to mitotic instability. The 8q24 region contains the imprinted KCNK9 gene, which is expressed from the maternal allele. Heterozygous KCNK9 mutations are associated with the imprinting disorder Birk-Barel syndrome. Here, we report a 2.5-year-old boy with developmental delay, microcephaly, dysmorphic features, diffuse muscle hypotonia, feeding problems, motor alalia and noncoarse neurogenic type of disturbance of muscle electrogenesis, partially overlapping with Birk-Barel syndrome phenotype. Cytogenetic analysis of lymphocytes revealed his karyotype to be 46,XY,r(8)(p23q24.3)[27]/45,XY,-8[3]. A de novo 7.9 Mb terminal 8p23.3p23.1 deletion, a 27.1 Mb 8p23.1p11.22 duplication, and a 4.4 Mb intact segment with a normal copy number located between them, as well as a 154-kb maternal LINGO2 gene deletion (9p21.2) with unknown clinical significance were identified by aCGH + SNP array. These aberrations were confirmed by real-time PCR. According to FISH analysis, the 8p23.1-p11.22 duplication was inverted. The ring chromosome originated from maternal chromosome 8. Targeted massive parallel sequencing did not reveal the KCNK9 mutations associated with Birk-Barel syndrome. Our data allow to assume that autosomal monosomy with inactive allele of imprinted gene arising from the loss of a ring chromosome in some somatic cells may be an etiological mechanism of mosaic imprinting disorders, presumably with less severe phenotype.


Assuntos
Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/metabolismo , Anormalidades Craniofaciais/metabolismo , Impressão Genômica/genética , Humanos , Deficiência Intelectual/metabolismo , Cariótipo , Cariotipagem/métodos , Masculino , Proteínas de Membrana/genética , Mosaicismo , Hipotonia Muscular/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Canais de Potássio de Domínios Poros em Tandem/genética , Cromossomos em Anel
16.
PLoS One ; 15(11): e0242263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33196683

RESUMO

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Many previous studies have demonstrated that the infiltrating of immune and stromal cells in the tumor microenvironment contributes significantly to prognosis. METHODS: Dataset TCGA-UVM, download from TCGA portal, was taken as the training cohort, and GSE22138, obtained from GEO database, was set as the validation cohort. ESTIMATE algorithm was applied to find intersection differentially expressed genes (DEGs) among tumor microenvironment. Kaplan-Meier analysis and univariate Cox regression model were performed on intersection DEGs to initial screen for potential prognostic genes. Then these genes entered into the validation cohort for validation using the same methods as that in the training cohort. Moreover, we conducted correlation analyses between the genes obtained in the validation cohort and the status of chromosome 3, chromosome 8q, and tumor metastasis to get prognosis genes. At last, the immune infiltration analysis was performed between the prognostic genes and 6 main kinds of tumor-infiltrating immune cells (TICs) for understanding the role of the genes in the tumor microenvironment. RESULTS: 959 intersection DEGs were found in the UM microenvironment. Kaplan-Meier and Cox analysis was then performed in the training and validation cohorts on these DEGs, and 52 genes were identified with potential prognostic value. After comparing the 52 genes to chromosome 3, chromosome 8q, and metastasis, we obtained 21 genes as the prognostic genes. The immune infiltration analysis showed that Neutrophil had the potential prognostic ability, and almost every prognostic gene we had identified was correlated with abundances of Neutrophil and CD8+ T Cell. CONCLUSIONS: Identifying 21 prognosis genes (SERPINB9, EDNRB, RAPGEF3, HFE, RNF43, ZNF415, IL12RB2, MTUS1, NEDD9, ZNF667, AZGP1, WARS, GEM, RAB31, CALHM2, CA12, MYEOV, CELF2, SLCO5A1, ISM1, and PAPSS2) could accurately identify patients' prognosis and had close interactions with Neutrophil in the tumor environment, which may provide UM patients with personalized prognosis prediction and new treatment insights.


Assuntos
Neoplasias Oculares/patologia , Melanoma/patologia , Microambiente Tumoral , Neoplasias Uveais/patologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Bases de Dados Genéticas , Neoplasias Oculares/genética , Neoplasias Oculares/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Serpinas/genética , Ubiquitina-Proteína Ligases/genética , Neoplasias Uveais/genética
17.
Exp Hematol ; 92: 62-74, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33152396

RESUMO

Acute myeloid leukemia development occurs in a stepwise fashion whereby an original driver mutation is followed by additional mutations. The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e., RUNX1, DNMT3A, TET2), while the secondary mutations often involve genes encoding members of signaling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. Expression of N822K-c-KIT strongly increases the self-renewal capacity of RUNX1-ETO-expressing cells. Global analysis of gene expression changes and alterations in the epigenome revealed that N822K-c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also revealed that double mutant cells still differ from their patient-derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumorigenesis.


Assuntos
Cromatina/metabolismo , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Transcrição Genética , Translocação Genética , Substituição de Aminoácidos , Cromatina/patologia , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/metabolismo , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Regulação Leucêmica da Expressão Gênica , Células HEK293 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas Proto-Oncogênicas c-kit/genética , Proteína 1 Parceira de Translocação de RUNX1/genética
18.
Nat Commun ; 11(1): 5070, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033260

RESUMO

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.


Assuntos
Linhagem da Célula , Biópsia Líquida , Neoplasias da Próstata/patologia , Líquidos Corporais/metabolismo , Cromossomos Humanos Par 8/genética , Células Clonais , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Filogenia
19.
Eur J Med Genet ; 63(12): 104082, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33059074

RESUMO

The loss of heterozygosity localized at chromosome segment 8p11.2 causes a contiguous gene syndrome, which mostly combined phenotype of Kallmann syndrome and hereditary spherocytosis. It has been documented that this combined phenotype is in association with both the deletion of the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes. Here, we described a 6-year-old girl with microcephaly, global developmental delay, mental retardation, and hereditary spherocytosis, associated with a heterozygous pathogenic microdeletion of 1.9 Mb size at 8p11.21. Molecular analysis confirmed that the identified microdeletion contained two OMIM (Online Mendelian Inheritance in Man)genes, including ANK1 and lysine acetyltransferase 6 A (KAT6A), but not FGFR1. Therefore, the simultaneous occurrence of mild developmental delay and distinctive facial in this patient was associated with the pathogenic variation of the KAT6A.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 8/genética , Deficiências do Desenvolvimento/genética , Histona Acetiltransferases/genética , Esferocitose Hereditária/genética , Anquirinas/genética , Criança , Transtornos Cromossômicos/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Esferocitose Hereditária/patologia
20.
Scand J Immunol ; 92(5): e12973, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32889730

RESUMO

Behçet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA-B*51, ERAP1, IL-10, IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-κB pathway suggesting new elements in the elusive BD etiopathogenesis.


Assuntos
Síndrome de Behçet/imunologia , Cromossomos Humanos Par 8/imunologia , NF-kappa B/imunologia , Trissomia/imunologia , Síndrome de Behçet/genética , Síndrome de Behçet/patologia , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Mucosa Bucal/imunologia , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fenótipo , Úlcera Cutânea/genética , Úlcera Cutânea/imunologia , Úlcera Cutânea/patologia , Trissomia/genética
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