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1.
Nat Commun ; 11(1): 3598, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680982

RESUMO

Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry. One such African ancestry specific rare variant, rs72725854 (A>G/T) (~6% allele frequency) has been associated with a ~2-fold increase in prostate cancer risk. However, the functional relevance of this variant is unknown. Here we show that the variant rs72725854 is present in a prostate cancer-specific enhancer at 8q24 locus. Chromatin-conformation capture and dCas9 mediated enhancer blocking establish a direct regulatory link between this enhancer and lncRNAs PCAT1, PRNCR1 and PVT1. The risk allele ('T') is associated with higher expression of PCAT1, PVT1 and c-myc in prostate tumors. Further, enhancer with the risk allele gains response to androgen stimulation by recruiting the transcription factor SPDEF whereas, non-risk alleles remain non-responsive. Elevated expression of these lncRNAs and c-myc in risk allele carriers may explain their greater susceptibility to prostate cancer.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 8/genética , Elementos Facilitadores Genéticos , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Alelos , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
2.
Am J Hum Genet ; 106(6): 846-858, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32470372

RESUMO

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.


Assuntos
Inversão Cromossômica/genética , Diabetes Mellitus/genética , Predisposição Genética para Doença , Hipertensão/genética , Obesidade/complicações , Obesidade/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Conjuntos de Dados como Assunto/normas , Diabetes Mellitus/patologia , Europa (Continente)/etnologia , Feminino , Perfilação da Expressão Gênica , Haplótipos , Humanos , Hipertensão/complicações , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Adulto Jovem
3.
Nat Commun ; 11(1): 1523, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251286

RESUMO

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.


Assuntos
Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Haplótipos , Heterozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias da Próstata/epidemiologia , Fatores de Proteção , Fatores de Risco
4.
Medicine (Baltimore) ; 99(14): e19730, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243411

RESUMO

RATIONALE: Co-occurrence of cytogenetic and molecular abnormalities is frequently seen in patients with acute myeloid leukemia (AML). The clinical outcome and genetic abnormalities of AML may vary; therefore, genetic investigation must be complex, using several techniques, to have an appropriate characterization of the AML genome and its clinical impact. The available molecular markers can predict prognosis only partially. Acute promyelocytic leukemia subtype M3 (AML M3) is a subtype of AML characterized by the presence of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) genes fusion. Targeted treatment with all-trans-retinoic acid (ATRA) and ATRA combined with arsenic trioxide significantly improved the survival of AML M3 patients. Unknown prognostic factors could contribute to the early death of these patients. PATIENT CONCERNS: We present the case of a young female (20 years old) patient, who presented at the emergency department 5 months after giving birth to her first child, complaining of asthenia, fatigue, general musculoskeletal pain, and fever (38°C), symptoms having been present for the previous 6 days. The patient denied any chronic diseases in her medical and family history. DIAGNOSIS: Laboratory analysis revealed severe pancytopenia. Cytogenetic and molecular analyzes revealed chromosomal abnormalities (trisomy 8), PML-RARA gene fusion, and fms-like tyrosine kinase 3 (FLT3) gene mutation. The immunophenotypic analysis was also suggestive for AML M3 according to the FAB classification. INTERVENTIONS: Specific treatment was initiated for AML M3 and for secondary conditions. Molecular and cytogenetic analyzes were performed to have a more detailed characterization of the patient's genome. OUTCOME: Seventy-two hours after admission, she developed psychomotor agitation, confusion, coma, and convulsion. Subsequent deterioration and early death were caused by intracerebral hemorrhage with multiple localization and diffuse cerebral edema. LESSONS: The presence of FLT3 internal tandem duplication (ITD) mutation may explain the rapid and progressive degradation of this AML M3 case and it may be used as a prognostic marker even when co-occuring with other markers such as PML-RARA gene fusion and trisomy 8. We consider that FLT3 ITD mutation analysis in young patients with AML should be performed as soon as possible. New strategies for patients' education, AML (or cancers in general) prevention, and treatment are needed.


Assuntos
Fusão Gênica/genética , Leucemia Mieloide Aguda/genética , Proteína da Leucemia Promielocítica/genética , Receptor alfa de Ácido Retinoico/genética , Trissomia/genética , Tirosina Quinase 3 Semelhante a fms/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Evolução Fatal , Feminino , Humanos , Mutação , Sequências de Repetição em Tandem , Adulto Jovem
5.
Pediatr Blood Cancer ; 67(7): e28341, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32323914

RESUMO

BACKGROUND: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. PROCEDURE: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. RESULTS: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. CONCLUSIONS: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 8/genética , Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Estudos Retrospectivos
6.
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
7.
Cytogenet Genome Res ; 160(1): 11-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31982875

RESUMO

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.


Assuntos
Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/ultraestrutura , Neutropenia/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Citogenética , Feminino , Marcadores Genéticos , Genótipo , Humanos , Cariotipagem , Linfócitos/metabolismo , Metáfase , Mosaicismo , Neutropenia/complicações , Neutropenia/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos , Úlceras Orais/complicações , Úlceras Orais/diagnóstico , Fenótipo , Estomatite Aftosa/complicações , Estomatite Aftosa/diagnóstico
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 44-47, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922595

RESUMO

OBJECTIVE: To explore the genetic basis for a family affected with congenital heart defects. METHODS: G-banding karyotyping, chromosomal microarray analysis (CMA) and multiplex ligation-dependent probe amplification (MLPA) were carried out to detect copy number variants in a patient with left ventricular noncompaction (LVNC) and his fetus. RESULTS: G-banding karyotyping showed the patient was 45,XY,rob(15;21)(q10;q10)[36]/46,XY[64], while the fetus had an normal karyotype. CMA revealed that both had arr[hg19]8p23.1(11 232 919-11 935 465)×1. MLPA showed both had deletion of all exons of the GATA4 gene. CONCLUSION: The LVNC of the patient and the ventricular septal defect(VSD) of his fetus may result from the same 8p23.1 deletion, for which GATA4 is probably the key gene.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 8 , Cardiopatias Congênitas , Cromossomos Humanos Par 8/genética , Fator de Transcrição GATA4/genética , Testes Genéticos , Cardiopatias Congênitas/genética , Humanos , Cariotipagem
11.
BMC Med Genomics ; 12(1): 197, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864361

RESUMO

BACKGROUND: Trisomy 8 mosaicism has a wide phenotypic variability, ranging from mild dysmorphic features to severe malformations. This report concluded a female pregnant woman with trisomy 8 mosaicism, and carefully cytogenetic diagnoses were performed to give her prenatal diagnostic information. This report also provides more knowledge about trisomy 8 mosaicism and the prenatal diagnostic for clinicians. CASE PRESENTATION: In this present study, we reported one case of pregnancy woman with trisomy 8 mosaicism. Noninvasive prenatal testing prompted an abnormal Z-score, but further three dimension color ultrasound result suggested a single live fetus with no abnormality. The phenotypic of the pregnant woman was normal. Based on our results, there were no abnormal initial myeloid cells (< 10- 4), which suggested that the patient had no blood diseases. The peripheral blood karyotype of the patient was 47,XX,+ 8[67]/46,XX [13], and karyotype of amniotic fluid was 46, XX. The next generation sequencing (NGS) result suggested that the proportions of trisomy 8 in different tissues were obviously different; and 0% in amniotic fluid. Last, the chromosomes of the patient and her baby were confirmed using chromosome microarray analysis (CMA), and the results were arr[GRCh37](8) × 3,11p15.5p13(230750-33,455,733) × 2 hmz and normal. CONCLUSIONS: This pregnancy woman was trisomy 8 mosaicism, but the phenotypic was normal, and also the fetus was normal. Carefully cytogenetic diagnoses should be performed for prenatal diagnose.


Assuntos
Cariotipagem , Diagnóstico Pré-Natal , Trissomia/diagnóstico , Trissomia/genética , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Adulto , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Mosaicismo , Fenótipo , Gravidez
12.
Rev. lab. clín ; 12(4): e75-e80, oct.-dic. 2019. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-187317

RESUMO

Introducción: La trisomía del cromosoma 8, conocida como síndrome de Warkany, es una rara enfermedad genética que cursa con un fenotipo muy variable. Su principal característica clínica es la discapacidad intelectual, facies dismórficas y pliegues plantares profundos. Presentamos el caso de un paciente de 10 años de edad, con facies gargoloides, retraso mental y rigidez en las articulaciones. El estudio inicial del cariotipo, en el que se analizaron 20 metafases, fue normal. Se solicitó array de polimorfismos de nucleótido único (SNPs) al laboratorio. Resultados: Se detectó una ganancia completa del cromosoma 8, que se interpretó como una trisomía 8 en mosaico de aproximadamente un 20%, y que era compatible con la clínica que presentaba el paciente. Discusión: Este caso muestra las limitaciones que tiene el análisis de solo 20 metafases en el cariotipo en pacientes con aneuploidías en mosaico. En estos casos estaría recomendado ampliar el estudio a al menos 30 metafases de cara a detectar mosaicismos en baja proporción


Introduction: Chromosome 8 trisomy, known as Warkany syndrome, is a rare genetic disease that has a very variable phenotype. Its main clinical characteristic is intellectual disability, dysmorphic facies, and deep plantar folds. The case is presented of a 10-year-old patient with gargoyle-like facies, mental retardation, and joint stiffness. The initial study of the karyotype, in which 20 metaphases were analysed, was normal. A single nucleotide polymorphisms (SNPs) array was requested from the laboratory. Results: A complete gain of chromosome 8 was detected, which was interpreted as a mosaic trisomy 8 of approximately 20%, and which was compatible with the clinical presentation of the patient. Discussion: This case shows the limitations of the analysis of only 20 metaphases in the karyotype in patients with mosaic aneuploidies. In these cases it would be recommended to extend the study to at least 30 metaphases in order to detect mosaicisms in low proportion


Assuntos
Humanos , Masculino , Pré-Escolar , Polimorfismo de Nucleotídeo Único/genética , Trissomia/genética , Cromossomos Humanos Par 8/genética , Mosaicismo , Achados Incidentais , Cariotipagem/métodos , Deficiência Intelectual/genética , Escoliose/diagnóstico
13.
Hum Genomics ; 13(1): 57, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753042

RESUMO

BACKGROUND: Chromosomal inversions are structural genetic variants where a chromosome segment changes its orientation. While sporadic de novo inversions are known genetic risk factors for cancer susceptibility, it is unknown if common polymorphic inversions are also associated with the prognosis of common tumors, as they have been linked to other complex diseases. We studied the association of two well-characterized human inversions at 17q21.31 and 8p23.1 with the prognosis of lung, liver, breast, colorectal, and stomach cancers. RESULTS: Using data from The Cancer Genome Atlas (TCGA), we observed that inv8p23.1 was associated with overall survival in breast cancer and that inv17q21.31 was associated with overall survival in stomach cancer. In the meta-analysis of two independent studies, inv17q21.31 heterozygosity was significantly associated with colorectal disease-free survival. We found that the association was mediated by the de-methylation of cg08283464 and cg03999934, also linked to lower disease-free survival. CONCLUSIONS: Our results suggest that chromosomal inversions are important genetic factors of tumor prognosis, likely affecting changes in methylation patterns.


Assuntos
Inversão Cromossômica/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG/genética , Metilação de DNA/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
14.
Hum Genomics ; 13(1): 54, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699156

RESUMO

BACKGROUND: The heat-shock transcription factor 1 (HSF1) has been linked to cell proliferation and survival in cancer and has been proposed as a biomarker for poor prognosis. Here, we assessed the role of HSF1 expression in relation to copy number alteration (CNA) and cancer prognosis. METHODS: Using 10,287 cancer genomes from The Cancer Genome Atlas and Cbioportal databases, we assessed the association of HSF1 expression with CNA and cancer prognosis. CNA of 8q24.3 was categorized as diploid (reference), deletion (fewer copies), gain (+ 1 copy) and amplification (≥ + 2 copies). Multivariate logistic regression modeling was used to assess 5-year survival among those with a first cancer diagnosis and complete follow-up data (N = 9568), categorized per anatomical location and histology, assessing interaction with tumor stage, and expressed as odds ratios and 95% confidence intervals. RESULTS: We found that only 54.1% of all tumors have a normal predicted 8q24.3 copy number and that 8q24.3 located genes including HSF1 are mainly overexpressed due to increased copies number of 8q24.3 in different cancers. The tumor of patients having respectively gain (+ 1 copy) and amplification (≥ + 2 copies) of 8q24.3 display a global increase of 5-year mortality (odds ratio = 1.98, 95% CI 1.22-3.21) and (OR = 2.19, 1.13-4.26) after full adjustment. For separate cancer types, tumor patients with 8q24.3 deletion showed a marked increase of 5-year mortality in uterine (OR = 4.84, [2.75-8.51]), colorectal (OR = 4.12, [1.15-14.82]), and ovarian (OR = 1.83, [1.39-2.41]) cancers; and decreased mortality in kidney cancer (OR = 0.41, [0.21-0.82]). Gain of 8q24.3 resulted in significant mortality changes in 5-year mortality for cancer of the uterus (OR = 3.67, [2.03-6.66]), lung (OR = 1.76, [1.24-2.51]), colorectal (OR = 1.75, [1.32-2.31]) cancers; and amplification for uterine (OR = 4.58, [1.43-14.65]), prostate (OR = 4.41 [3.41-5.71]), head and neck (OR = 2.68, [2.17-3.30]), and stomach (OR = 0.56, [0.36-0.87]) cancers. CONCLUSIONS: Here, we show that CNAs of 8q24.3 genes, including HSF1, are tightly linked to 8q24.3 copy number in tumor patients and can affect patient outcome. Our results indicate that the integration of 8q24.3 CNA detection may be a useful predictor for cancer prognosis.


Assuntos
Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA/genética , Fatores de Transcrição de Choque Térmico/genética , Neoplasias/genética , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Resultado do Tratamento
15.
Am J Hum Genet ; 105(5): 1057-1068, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668705

RESUMO

Average arterial oxyhemoglobin saturation during sleep (AvSpO2S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10-7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.


Assuntos
Cromossomos Humanos Par 8/genética , Proteínas Ativadoras de GTPase/genética , Oxiemoglobinas/genética , Sono/genética , Proteínas Supressoras de Tumor/genética , Ligação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Sequenciamento Completo do Genoma/métodos
16.
Science ; 366(6463)2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31624180

RESUMO

Copy number variants (CNVs) are subject to stronger selective pressure than single-nucleotide variants, but their roles in archaic introgression and adaptation have not been systematically investigated. We show that stratified CNVs are significantly associated with signatures of positive selection in Melanesians and provide evidence for adaptive introgression of large CNVs at chromosomes 16p11.2 and 8p21.3 from Denisovans and Neanderthals, respectively. Using long-read sequence data, we reconstruct the structure and complex evolutionary history of these polymorphisms and show that both encode positively selected genes absent from most human populations. Our results collectively suggest that large CNVs originating in archaic hominins and introgressed into modern humans have played an important role in local population adaptation and represent an insufficiently studied source of large-scale genetic variation.


Assuntos
Introgressão Genética , Animais , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Evolução Molecular , Genoma Humano , Haplótipos , Hominidae/genética , Humanos , Melanesia , Modelos Genéticos , Homem de Neandertal/genética , Polimorfismo Genético , Seleção Genética , Sequenciamento Completo do Genoma
17.
J Cancer Res Clin Oncol ; 145(12): 2911-2920, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646374

RESUMO

OBJECTIVE: To investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer. METHODS: Peripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy. RESULTS: Before treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim+ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim+ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim+ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim+ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim+ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239-6.131; p = 0.013]. CONCLUSIONS: This study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim+ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim+ CTCs is correlated with liver metastases and may help predict poor PFS.


Assuntos
Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/metabolismo , Vimentina/metabolismo , Cromossomos Humanos Par 8/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos
18.
Cytogenet Genome Res ; 159(2): 81-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31614359

RESUMO

Lipoblastoma is a rare benign neoplasm with overlapping histology with other lipomatous tumors. Genetic aberrations including translocations of 8q and splitting of the PLAG1 probe leading to "promoter swapping" and gains of chromosome 8 or PLAG1 foci have been described in lipoblastoma. Here, we report 3 lipoblastomas revealing novel genetic aberrations involving PLAG1: a high level of PLAG1 amplification up to 50 copies in a 4-year-old girl with recurrence of a right flank mass, a partial deletion of PLAG1 with the flanking junction breakpoints involving the 3'PLAG1 and 5'HAS2 genes in a 17-month-old boy with a retroperitoneal mass, and an insertion of 2q31 into 8q11.2 and translocation of 8q to 2q with the latter translocated onto 12q leading to separation of the PLAG1 FISH probe in a 5-year-old girl with a left back mass. Our novel cytogenetic findings further expand the mechanisms of PLAG1 transcriptional upregulation in lipoblastoma pathogenesis.


Assuntos
Proteínas de Ligação a DNA/genética , Lipoblastoma/genética , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Análise Citogenética/métodos , Feminino , Humanos , Lactente , Masculino , Translocação Genética/genética
19.
Rinsho Ketsueki ; 60(9): 1157-1165, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597839

RESUMO

The 8p11 myeloproliferative syndrome (EMS) is a relatively rare hematological malignancy defined by the presence of chromosomal abnormalities associated with fibroblast growth factor-1 gene, located in the 8p11-12.1 chromosomal locus. To date, only around a hundred cases have been reported in the literature. Patients with EMS present with various forms of myeloid/lymphoid malignancies, such as myeloproliferative neoplasms, acute myeloid leukemia, and T- or B-linage lymphoblastic lymphoma, which are frequently associated with eosinophilia. Prognosis of EMS is poor and a standard treatment strategy has not yet been established. In contrast to myeloid/lymphoid neoplasms associated with PDGFR-A or PDGFR-B rearrangement, the tyrosine kinase inhibitor (TKI) imatinib is not an effective therapeutic option for EMS patients. Other types of TKI, i.e., PKC412, sorafenib, ponatinib, dasatinib, and dovitinib, show growth-inhibitory effects against the cells harboring several types of FGFR-1 fusion genes in in vitro studies; however, the usefulness of either drug has not been confirmed by clinical trials. Therefore, at present, allo-hematopoietic stem cell transplantation is the only curative methods for EMS. Very recently, a phase-2 study with pemigatinib, an inhibitor for FGFR1, showed clinical benefits for EMS patients, including major cytogenetic response, suggesting a new therapeutic option for EMS.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Ensaios Clínicos Fase II como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores
20.
Nat Commun ; 10(1): 4495, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582743

RESUMO

Aneuploidy is a major source of gene dosage imbalance due to copy number alterations (CNA), and viable human trisomies are model disorders of altered gene expression. We study gene and allele-specific expression (ASE) of 9668 single-cell fibroblasts from trisomy 21 (T21) discordant twins and from mosaic T21, T18, T13 and T8. We examine 928 single cells with deep scRNAseq. Expected and observed overexpression of trisomic genes in trisomic vs. diploid bulk RNAseq is not detectable in trisomic vs. diploid single cells. Instead, for trisomic genes with low-to-average expression, their altered gene dosage is mainly due to the higher fraction of trisomic cells simultaneously expressing these genes, in agreement with a stochastic 2-state burst-like model of transcription. These results, confirmed in a further analysis of 8740 single fibroblasts with shallow scRNAseq, suggest that the specific transcriptional profile of each gene contributes to the phenotypic variability of trisomies. We propose an improved model to understand the effects of CNA and, generally, of gene regulation on gene dosage imbalance.


Assuntos
Variações do Número de Cópias de DNA , Dosagem de Genes , Modelos Genéticos , Transcriptoma/genética , Trissomia/genética , Alelos , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 8/genética , Síndrome de Down/genética , Feminino , Fibroblastos , Perfilação da Expressão Gênica , Humanos , Masculino , Mosaicismo , Fenótipo , RNA-Seq , Análise de Célula Única
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