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1.
Anticancer Res ; 40(1): 97-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892557

RESUMO

BACKGROUND/AIM: Chronic expanding hematoma is defined as a hematoma that gradually expands over 1 month or longer, is without neoplastic features on histological sections, and does not occur in the setting of coagulopathy. The pathogenetic mechanism behind its development is unknown, nor is anything known about its genetic features. CASE REPORT: A 49-year-old man noted a tender lump close to the right femoral trochanter. Examination of a core needle biopsy showed a fibrous capsule with fibrinoid material on one side. The patient underwent surgery with removal of a cystic, encapsulated structure with central bleeding and proliferating vessels in the fibrous capsule. The reactive fibroblasts were without any sign of atypia. Genetic analyses were performed on this chronic expanding hematoma. RESULTS: G-Banding analysis of short-term cultured cells from the chronic expanding hematoma yielded a karyotype with a single clonal chromosome abnormality: 46,XY,t(11;19)(q13;q13)[8]/46,XY[10]. RNA sequencing and examination of the sequencing data using five different programs did not identify fusion genes related to the translocation. CONCLUSION: The acquired translocation t(11;19)(q13;q13) suggested that chronic expanding hematoma is a neoplastic lesion. Since the translocation did not lead to any fusion genes, one can speculate that it causes deregulation of gene expression.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 19 , Estudos de Associação Genética , Predisposição Genética para Doença , Hematoma/diagnóstico , Hematoma/genética , Translocação Genética , Biópsia , Bandeamento Cromossômico , Doença Crônica , Progressão da Doença , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade
2.
Zhonghua Er Ke Za Zhi ; 58(1): 35-40, 2020 Jan 02.
Artigo em Chinês | MEDLINE | ID: mdl-31905474

RESUMO

Objective: To investigate the genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy (DEE). Methods: Clinical data including the manifestations and electroencephalogram of 8 children with KCNA2 variants treated in the Department of Pediatrics, Peking University First Hospital from March 2017 to June 2019 were collected and analyzed retrospectively. Results: Among the 8 epileptic patients with KCNA2 variants, 5 were males and 3 were females. The age of onset was from 1 day to 11 months. The age at last follow-up ranged from 4 months to 86 months. Two variants including c.1214C>T (loss-of-function) and c.1120A>G (gain-and loss-of-function) were identified. The variant of c.1214C>T was found in six patients (case 1-6). For these patients, the age of onset was from 5 to 11 months and they were characterized by multiple seizure types. All had focal seizures and had normal development before seizure onset with developmental regression after seizure onset. The first electroencephalogram showed epileptic discharges in Rolandic region in two, epileptic discharges in Rolandic region combined with generalized discharge in one, generalized discharge with posterior predominance in two (combined with or transferred to Rolandic region during the course) and epileptic discharges in posterior region combined with generalized discharge in one. And in 5 of them the Rolandic discharges developed into epileptic electrical status (ESES) during sleep. All the six patients were still treated with a combination of multiple antiepileptic drugs. Two of them had seizure controlled at 80 months and 68 months, respectively. The variant of c.1120A>G were identified in two of eight patients (case 7 and 8) and they had seizure onset on the 1st day after birth. Their epileptic seizures were frequent and difficult to control. They had remarkably developmental delay and microcephaly since birth. One case (case 8) had a wide forehead. They had frequent seizures up to the last follow-up. In case 7, the early electroencephalogram showed epileptic discharges in temporal region, and interictal electroencephalogram at 3 months of age showed multifocal discharge with posterior and temporal region predominance. In case 8, the early electroencephalogram was normal and electroencephalogram showed burst suppression at 2 months of age, and it developed epileptiform discharge in posterior region at 1 year of age. Conclusions: KCNA2 gene variants can lead to DEE with multiple seizures types. Among them, loss-of-function c.1214C>T is the most common, and these patients have seizure onset at infancy with Rolandic discharges tended to develop into to ESES pattern. The variant of c.1120A>G is a gain-of- and loss-of-function variant, patients with c.1120A>G have seizure onset in neonatal period, the phenotype overlaps with the former but is more severe.


Assuntos
Encefalopatias/genética , Epilepsia/diagnóstico , Canal de Potássio Kv1.2/genética , Convulsões , Idade de Início , Encéfalo/fisiopatologia , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/complicações , Epilepsia/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Estudos Retrospectivos
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 1-4, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922584

RESUMO

OBJECTIVE: To explore susceptibility genes for autism spectrum disorders (ASD). METHODS: Whole-exome sequencing was carried out for 60 family trios affected with sporadic ASD. Genetic variants discovered in over 10% of the patients were selected for genotype-phenotype correlation and pathway enrichment analysis using Phenolyzer software and metascape database. Combining gene-phenotypic scores, pathway-related genes associated with neural and neurite triggering were screened for the candidates. RESULTS: A total of 170 common variants were found to be associated with the ASD phenotype. Among these, there was only one high-confidence gene [SHANK2(0.8146)] and four medium-confidence genes [ERBB2(0.1322), LAMC3(0.1117), PPFIA4(0.1059), DISC1(0.1002)]. Twenty-pathways and four biological processes were found to be statistically significant by pathway enrichment analysis, which included neuron projection morphogenesis (GO: 0048812), regulation of neuroblast proliferation (GO: 1902692), modulation of excitatory postsynaptic potential (GO: 0098815), and dendrite morphogenesis (GO: 0048813). Twenty-one genes were found to be closely associated with neurological and neurite triggering, among which only SHANK2, ERBB2, and DISC1 had above-medium confidence correlation scores with the ASD phenotypes. CONCLUSION: Abnormal neuron projection morphogenesis (GO: 0048812) may be closely related to the occurrence of ASD. SHANK2, ERBB2, and DISC1 are susceptibility genes for ASD.


Assuntos
Transtorno do Espectro Autista , Variação Genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Humanos , Fenótipo , Sinapses/genética , Sequenciamento Completo do Exoma
4.
Hum Genet ; 139(1): 95-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31317254

RESUMO

A central goal in human genetics is the identification of variants and genes that influence the risk of polygenic diseases. In the past decade, genome-wide association studies (GWAS) have identified tens of thousands of genetic loci associated with various diseases. Since the majority of such loci lie within non-coding regions and have many candidate variants in linkage disequilibrium, it has been challenging to accurately identify specific causal variants and genes. To aid in their discovery a variety of statistical and experimental approaches have been developed. These approaches often borrow information from functional genomics assays such as ATAC-seq, ChIP-seq and RNA-seq to annotate functional variants and identify regulatory relationships between variants and genes. While such approaches are powerful, given the diversity of cell types and environments, it is paramount to select disease-relevant contexts for follow-up analyses. In this review, we discuss the latest developments, challenges, and best practices for determining the causal mechanisms of polygenic disease risk variants with functional genomics data from specialized cell types.


Assuntos
Linhagem da Célula/genética , Genes/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genômica/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Predisposição Genética para Doença , Humanos
5.
Gene ; 726: 144147, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31629822

RESUMO

BACKGROUND: Suicidal ideation (SI) is the most serious symptom of major depressive disorder (MDD) and considered an extreme state. The serotonin transporter gene (SLC6A4) plays a significant role in MDD and suicide pathophysiology. Previous studies have revealed an association between common variants of SLC6A4 with the risk of MDD and suicide. However, very few studies have so far focused on the degree to which rare variants of SLC6A4 are responsible for the depression observed in adolescent and young adult suicide patients. The aim of this study was to examine the impact of common and rare variants of SLC6A4 on the risk of Han Chinese adolescents and young adults suffering MDD with SI. METHODS: Targeted sequencing of the SLC6A4 gene was conducted using FastTarget technology in Han Chinese adolescents and young adults, of which 74 were MDD patients with SI and 150 were healthy controls. Gene-based association analyses of rare variants were performed using enrichment analysis and a cumulative allele test. An allele association study was performed against common variants. RESULTS: After sequencing and bioinformatics analysis, a total of 15 single nucleotide variants (SNVs) were detected in the targeted regions from all participants, including 9 common and 6 rare variants. Among these, 5 rare variants were identified within the study group. Enrichment analysis of rare variants demonstrated a statistical difference (p = 0.042) between the study and control groups. Using cumulative allele analysis, alternative alleles in the SLC6A4 gene exhibited an association with MDD patients with SI (cumulative allele: OR = 10.18, 95% CI = 1.18-87.32, p = 0.017). No significant association was found between the 9 common SLC6A4 variants and MDD patients with SI. CONCLUSIONS: Our results suggest that rare variants of SLC6A4 may contribute to a genetic risk of adolescents and young adults suffering MDD with SI.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Alelos , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Fatores de Risco , Ideação Suicida , Suicídio , Adulto Jovem
6.
Gene ; 726: 144173, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669639

RESUMO

A recent study published in GENE performed a meta-analysis on the relationship between genetic variant rs895819 in microRNA-27a and risk of stomach neoplasms, and the results indicated an association of rs895819 with increased risk of stomach neoplasms in heterogenous model among Chinese. However, the meta-analysis did not include one large sample size of study that met inclusion criteria. When including all related studies, our meta-analysis showed no significant association of rs895819 with stomach neoplasms risk in each different model in all population, Chinese and Europeans. Thus, pooling all related studies did not provide evidence on the association of rs895819 with increased risk of stomach neoplasms.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , MicroRNAs/genética , Fatores de Risco
7.
Gene ; 728: 144185, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31838252

RESUMO

BACKGROUND: MiR-27a rs895819 polymorphism is considered as a tumor- related susceptibility gene. Previous meta-analyses evaluated the association the association between miR-27a rs895819 and cancer risk, but the results were inconsistent. The present meta-analysis was carried out to better estimate the correlation of rs895819 and cancer susceptibility. METHODS: We searched several databases to identify relevant studies, including PubMed, EMBASE and the Cochrane Controlled Trials Register. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the association between miR-27a rs895819 and cancer risk. RESULTS: The overall analysis showed the miR-27a rs895819 was not associated with cancer susceptibility in all models (dominant model: OR = 1.02, 95% CI:0.94-1.10, p = 0.632; recessive model: OR = 1.05, 95% CI: 0.92-1.76, p = 0.474; homozygote model: OR = 1.06, 95% CI: 0.91-1.23, p = 0.439; heterozygote model: OR = 1.00, 95% CI: 0.93-1.08, p = 0.934; and allele model: OR = 1.02, 95% CI: 0.96-1.09, p = 0.486). Interestingly, rs895819 A > G was significantly associated with colorectal cancer risk in recessive model (OR = 1.54, 95% CI: 1.29-1.83, p < 0.001), homozygote model (OR = 1.59, 95% CI: 1.31-1.92, p < 0.001), and allele model (OR = 1.22, 95% CI: 1.10-1.34, p < 0.001). In addition, rs895819 polymorphism was correlated with increased risk of breast cancer in the recessive model (OR = 0.81, 95% CI: 0.66-1.00, p = 0.046) and allele model (OR = 0.89, 95% CI: 0.80-0.98, p = 0.021). CONCLUSIONS: Our results suggested that rs895819 polymorphism was correlated with increased risk of colorectal cancer and breast cancer, but not all types of cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/patologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Prognóstico , Fatores de Risco
8.
Vasc Endovascular Surg ; 54(2): 175-181, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31746280

RESUMO

Nail-patella syndrome (NPS) is a rare disorder characterized by abnormal development of ectodermal and mesodermal tissues. Classically, NPS presents as a triad of nail dysplasia, dysplastic patellae, and bony exostoses of the ilia known as "iliac horns." Apart from dermatological and skeletal abnormalities, patients may also have involvement of ophthalmologic and renal systems. The underlying molecular etiology in NPS is the mutation of LMX1B homeobox gene which results in loss of function of its protein also called LMX1B, a DNA-binding protein belonging to the larger LIM-homeodomain transcription factor family. Normal LMX1B gene and protein function are essential for dorsalization of the vertebrate limb bud, development of anterior eye structures, skull formation, and differentiation and migration of neurons in the central nervous system. We report a case of confirmed NPS presenting with congenital aplasia of the internal carotid artery and believe this is the first report of cerebrovascular developmental abnormality associated with NPS.


Assuntos
Artéria Carótida Interna/anormalidades , Malformações Vasculares do Sistema Nervoso Central/genética , Proteínas com Homeodomínio LIM/genética , Mutação , Síndrome da Unha-Patela/genética , Fatores de Transcrição/genética , Artéria Carótida Interna/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome da Unha-Patela/diagnóstico , Fenótipo
9.
Lancet Haematol ; 7(1): e73-e81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810765

RESUMO

Diagnosing, surveilling, and understanding the biological consequences of clonal haematopoiesis poses a clinical challenge for both patients and clinicians. The relationship between peripheral blood cytopenias and myeloid neoplasms-such as myelodysplastic syndrome-is an area of active research, and understanding of clonal haematopoiesis has developed markedly on the basis of findings concerning somatic mutations in genes known to be associated with myelodysplastic syndrome. These findings have raised the conundrum of how to appropriately define and follow myelodysplastic syndrome precursor states, such as clonal haematopoiesis of indeterminate potential (CHIP) and clonal cytopenias of undetermined significance (CCUS). Identifying these conditions could allow earlier diagnosis of myelodysplastic syndrome, modify surveillance for myelodysplastic syndrome, and possibly guide therapies, but this information also comes at a cost to patients that might or might not be justified by our present understanding of clonal haematopoiesis. When faced with a diagnosis of clonal haematopoiesis, some patients and providers might be content to let the events unfold naturally, whereas others may insist on intense follow-up and early interventions. This Viewpoint assesses recent developments in clonal haematopoiesis and the related implications for affected patients and their providers.


Assuntos
Hematopoese , Síndromes Mielodisplásicas/diagnóstico , Transformação Celular Neoplásica/genética , Predisposição Genética para Doença , Humanos , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/fisiopatologia
10.
Gene ; 726: 144165, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726085

RESUMO

GWAS studies have identified variant rs 17810546 in a non-coding region on chromosome 3 as a risk factor for several auto-immune diseases, including Celiac Disease. In silico analysis reveals that this variant is located in a transcription regulatory site. By means of reporter constructs we show that this region can override the expression rate of a gene as determined by its native promoter and that this modulation is influenced by the genetic composition of the haplotype which rs17810546 forms with a nearby other variant, rs761008. Secondly, we present data that this genetically imprinted modulation could be involved in Celiac Disease through the IL12A gene which is located 40 Kb downstream of this regulatory region. Based on our findings it is most likely that the IL12A gene does so as part of the cytokine IL-35.


Assuntos
Doença Celíaca/genética , Inativação Gênica/fisiologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Linhagem Celular , Estudo de Associação Genômica Ampla/métodos , Células HEK293 , Haplótipos/genética , Humanos , Interleucinas/genética , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética
11.
Hum Genet ; 139(1): 85-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520123

RESUMO

In recent years, genome-wide association study (GWAS) sample sizes have become larger, the statistical power has improved and thousands of trait-associated variants have been uncovered, offering new insights into the genetic etiology of complex human traits and disorders. However, a large fraction of the polygenic architecture underlying most complex phenotypes still remains undetected. We here review the conditional false discovery rate (condFDR) method, a model-free strategy for analysis of GWAS summary data, which has improved yield of existing GWAS and provided novel findings of genetic overlap between a wide range of complex human phenotypes, including psychiatric, cardiovascular, and neurological disorders, as well as psychological and cognitive traits. The condFDR method was inspired by Empirical Bayes approaches and leverages auxiliary genetic information to improve statistical power for discovery of single-nucleotide polymorphisms (SNPs). The cross-trait condFDR strategy analyses separate GWAS data, and leverages overlapping SNP associations, i.e., cross-trait enrichment, to increase discovery of trait-associated SNPs. The extension of the condFDR approach to conjunctional FDR (conjFDR) identifies shared genomic loci between two phenotypes. The conjFDR approach allows for detection of shared genomic associations irrespective of the genetic correlation between the phenotypes, often revealing a mixture of antagonistic and agonistic directional effects among the shared loci. This review provides a methodological comparison between condFDR and other relevant cross-trait analytical tools and demonstrates how condFDR analysis may provide novel insights into the genetic relationship between complex phenotypes.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Humanos , Fenótipo
12.
Gut ; 69(1): 103-111, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31023832

RESUMO

OBJECTIVE: We assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival. DESIGN: We sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response. RESULTS: Serial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1-2). CRP peaked 3-5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I-III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77). CONCLUSIONS: CRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/cirurgia , Vitamina D/análogos & derivados , Idoso , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores de Calcitriol/genética , Análise de Sobrevida , Síndrome de Resposta Inflamatória Sistêmica/sangue , Vitamina D/sangue
13.
J Clin Pathol ; 73(1): 17-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31300530

RESUMO

OBJECTIVE: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management. METHODS: Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed. RESULTS: High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20-89) with the two patients <45 years of age showing highest intratumour heterogeneity. TP53 was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance (KIT S821F, KIT T670I, RAS mutations at codons 12 and 13). CONCLUSION: We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.


Assuntos
Biomarcadores Tumorais/genética , Heterogeneidade Genética , Neoplasias de Cabeça e Pescoço/genética , Mutação , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Tomada de Decisão Clínica , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Seleção de Pacientes , Fenótipo , Medicina de Precisão , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma
14.
J Clin Pathol ; 73(1): 7-13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31422373

RESUMO

AIMS: Hereditary protein S (PS) deficiency is one of the natural anticoagulant deficiencies causing thrombophilia. We herein described a young male with recurrent deep venous thrombosis, who was diagnosed as type I PS deficiency with compound heterozygous mutations of PROS1 gene. We aimed to analyse the relationship between the genotype and phenotype detection and investigate the pathological mechanisms of PROS1 mutations causing PS deficiency. METHODS: Genetic analysis of PROS1 gene was carried out by direct sequencing. Thrombin generation potential and the inhibition function of thrombin generation by plasma PS were detected by thrombin generation test (TGT). The mRNA transcription level of mutant PS in vitro was measured by real-time PCR, while the protein level was evaluated by western blot and ELISA. Cellular distribution of the protein was further analysed by immunofluorescence. RESULTS: Compound heterozygous mutations (PROS1 c.1551_1552delinsG, p.Thr518Argfs*39 and PROS1 c.1681C>T, p.Arg561Trp) were identified in the propositus, and the former one was a novel small indel mutation. TGT results showed impaired inhibition of thrombin generation with the addition of activated protein C in his parents with certain heterozygous mutations. In vitro expression study, p.Thr518Argfs*39 mutant produced truncated protein retained in the cytoplasm, while p.Arg561Trp mutant partially affected the secretion of PS. Both mutations are located in C-terminal sex hormone-binding globulin (SHBG)-like domain of PS. CONCLUSIONS: Compound heterozygous mutations identified in the study have strong detrimental effect, causing severe type I PS deficiency in the propositus. SHBG-like domain of PS might play an important role in PS secretion system.


Assuntos
Coagulação Sanguínea/genética , Proteínas Sanguíneas/genética , Heterozigoto , Mutação , Deficiência de Proteína S/genética , Trombose Venosa/genética , Adulto , Proteínas Sanguíneas/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Deficiência de Proteína S/sangue , Deficiência de Proteína S/diagnóstico , Recidiva , Via Secretória , Índice de Gravidade de Doença , Trombina/metabolismo , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
15.
J Clin Pathol ; 73(1): 14-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31434698

RESUMO

AIMS: Untranslated regions (UTRs) play an important role in post-transcriptional regulation of gene expression, including by modulating messenger RNA (mRNA) transport out of the nucleus, translation efficiency, subcellular localisation and stability. Any mutation in this region could alter the stability of mRNA and thereby affect protein synthesis. We analysed if a mutation located in the α complex protected region of the α1 globin gene could cause non-deletional α-thalassaemia by affecting post-transcriptional stability (mRNA stability). METHODS: A total of 14 patients without anaemia, normal or slight microcytosis and hypochromia (medium concentration haemoglobin [MCH] <27 pg) were studied. Haemoglobin subtypes were screened using capillary zone electrophoresis and ion-exchange high-performance liquid chromatography (VARIANT II ß-Thalassaemia Short Program). The most common α-globin mutations were identified by multiplex PCR (Alpha-Globin StripAssay kit) and the molecular characterisation by automatic sequencing of alpha globin genes. RESULTS: All of them shown a novel transversion mutation in nt 778 (C>A), which is located in the 3' UTR in the α complex protected region [HBA1: c.*+46C>A]. CONCLUSIONS: This mutation is in the αRNAmin binding site, so a single nucleotide substitution in this region can decrease mRNA stability by potentially compromising the binding of α-complex protein to αRNAmin, favouring the decay of α-globin mRNA via erythroid cell-enriched endoribonuclease cleavage. In this case, it is a non-deletional α-thalassaemia. However, in silico and empirical studies predicted that it could be a silent polymorphism. Functional studies should be carried out to confirm whether it is a pathological mutation or a silent polymorphism.


Assuntos
Regiões 3' não Traduzidas , Mutação , Polimorfismo Genético , Estabilidade de RNA , RNA Mensageiro/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Fenótipo , RNA Mensageiro/metabolismo , Fatores de Risco , alfa-Globinas/metabolismo , Talassemia alfa/sangue , Talassemia alfa/diagnóstico
16.
J Clin Pathol ; 73(1): 51-56, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662438

RESUMO

Fibroepithelial tumours are biphasic neoplasms of the breast comprising the common benign fibroadenomas and the less common phyllodes tumours (PTs), which have recurrent potential. PTs are classified into benign, borderline or malignant, based on five histopathological criteria, with malignant PTs having the highest metastatic capability. Accurate diagnosis can be challenging due to the subjective assessment of histopathological parameters. Fibroadenomas bear morphological similarities to benign PTs, while borderline and malignant PTs can sometimes be difficult to distinguish from other spindle cell tumours of the breast. From clonality studies to whole-genome sequencing, much research has been conducted to elucidate the molecular pathogenesis of fibroepithelial tumours, which, in turn, have allowed leveraging the findings for diagnostic applications, including grading of PTs. The most noteworthy discovery was of recurrent MED12 mutations in both fibroadenomas and PTs. Subsequent studies also uncovered relatively frequent genetic mutations in TERT promoter and RARA A customised panel of 16 most frequently mutated genes in fibroepithelial tissues has been compiled previously and has contributed to resolving a few diagnostic dilemmas. This review will introduce the 16 genes and focus on the top three that are most frequently mutated in fibroepithelial tumours: MED12, TERT, and RARA.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Complexo Mediador/genética , Mutação , Neoplasias Fibroepiteliais/genética , Receptor alfa de Ácido Retinoico/genética , Telomerase/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Humanos , Taxa de Mutação , Neoplasias Fibroepiteliais/patologia , Fenótipo , Fatores de Risco , Transcriptoma
17.
Gene ; 725: 144163, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639433

RESUMO

BACKGROUND: Previous studies have established that coronary artery disease is associated with excess inflammation. These studies have shown an elevation of both pro and anti-inflammatory cytokines in sufferers of coronary artery disease. There is increasing interest in the role played by the inflammasome Nod Like Receptor family pyrin domain containing 3 (NLRP3) in the aetiology of coronary artery disease. Increased severity of coronary artery disease correlates with higher levels of expression of NLRP3. Does NLRP3 polymorphisms play a role in the aetiology of coronary artery disease? METHOD: In a cohort of Vietnam War (n-299) veterans who have been previously exposed to trauma, NLRP3 polymorphisms were analysed for association with coronary calcium scores using analyses of variance. Independent t-test was used to analyse genotypes. In samples with a small representation of minor homozygotes, genotypes were combined and analysed using independent t-test. If any of the genotype analysis suggested the potential for a dominant or a recessive model the model was further explored. Hardy-Weinberg Equilibrium was calculated using Hardy-Weinberg equilibrium calculator including analysis for ascertainment bias. RESULTS: The NLRP3 polymorphism, rs10159239 was significantly associated (p = 0.001) with a higher raised coronary calcium score. The Single Nucleotide Polymorphism rs10159239 was examined by logistic regression with known risk factors for Coronary artery disease and remained significant (0.035). This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. CONCLUSIONS: This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. Further research is needed to replicate our results in larger well-characterised cohorts.


Assuntos
Doença da Artéria Coronariana/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alelos , Proteínas de Transporte/genética , Estudos de Coortes , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Veteranos , Guerra do Vietnã
18.
Zhonghua Nei Ke Za Zhi ; 59(1): 23-28, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887832

RESUMO

Objective: To investigate the association of GNA11 gene polymorphisms with the risk of adult-onset non-surgical hypoparathyroidism (Ns-HypoPT). Methods: Genotyping of GNA11 single nucleotide polymorphisms (SNPs) (rs28685098, rs4806907, rs11084997 and rs78003011) was carried out in 203 patients and 209 healthy participants by sequenom MassArray iPLEX System. These SNPs are located in promoter and 3'untranslated region (3'UTR) of GNA11 gene, respectively. Results: Allele and genotype frequencies of rs11084997 in patients were significantly different from those of controls (genotype GG:60.5% vs. 49.8%, GC: 35.5% vs. 41.6%, CC: 4.0% vs. 8.6%, P=0.038; G allele 78.3% vs. 70.6%, C allele 21.7% vs. 29.4%, P=0.012), and the C allele of rs11084997 carriers had a lower risk to develops Ns-HypoPT in additive and dominant genetic models [OR=0.382 (0.160-0.915), 0.647 (0.437-0.957)]. CC-Haplotype formed by the minor alleles of rs4806907 and rs11084997 was associated with a decreased risk of Ns-HypoPT in additive, dominant and recessive genetic model [OR=0.317 (0.126-0.801), 0.640 (0.430-0.952), 0.367 (0.148-0.912)]. Conclusion: The minor allele C of rs11084997 in GNA11 gene promoter was associated with decreased risk of Ns-HypoPT in Chinese population.


Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Hipoparatireoidismo/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Frequência do Gene , Genótipo , Humanos , Hipoparatireoidismo/diagnóstico , Polimorfismo de Nucleotídeo Único
19.
Equine Vet J ; 52(1): 34-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30903710

RESUMO

BACKGROUND: Belgian horses are commonly affected with ocular squamous cell carcinoma (SCC), the most common cancer of the equine eye. A missense mutation in damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) has been established as a recessive genetic risk factor for ocular SCC in the Haflinger breed. A sample of Belgian horses with unknown SCC phenotype was shown to possess this variant at a similar frequency to the Haflinger breed. Retrospective studies indicate that chestnut coat colour may predispose to the development of SCC. OBJECTIVES: To determine if DDB2 c.1013C>T is a risk factor for ocular SCC in a strictly phenotyped sample of Belgian horses. To investigate associations between coat colour loci genotypes and ocular SCC. STUDY DESIGN: Retrospective and prospective case identification, genetic investigation. METHODS: Genomic DNA was isolated from blood, hair or formalin-fixed paraffin-embedded tissue from 25 Belgian horses with histologically confirmed ocular SCC and 18 unaffected Belgian horses. Association testing of 34 single nucleotide variants from 11 genomic loci and genotyping for DDB2 c.1013C>T and coat colour alleles were performed. Exons of DDB2 were sequenced in four cases and two controls. Associations were analysed by Chi-square or Fisher's exact tests and relative risk was calculated. RESULTS: Homozygosity for DDB2 c.1013C>T was significantly associated with ocular SCC (P = 7.4 × 10-7 ). Seventy-six per cent of affected horses were homozygous for the variant. Relative risk for homozygous horses developing SCC was 4.0 (P = 1.0 × 10-4 ). Sequencing DDB2 did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified. MAIN LIMITATIONS: Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut, so association with this MC1R variant could not be investigated. CONCLUSIONS: A missense variant, DDB2 c.1013C>T, p.Thr338Met, is a risk factor for ocular SCC in Belgian horses. A genetic risk test is commercially available.


Assuntos
Carcinoma de Células Escamosas/veterinária , Proteínas de Ligação a DNA/genética , Neoplasias Oculares/veterinária , Predisposição Genética para Doença , Doenças dos Cavalos/genética , Mutação de Sentido Incorreto , Animais , Cavalos
20.
Gut ; 69(1): 7-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672839

RESUMO

BACKGROUND AND AIM: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). METHODS: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed. RESULTS: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions. CONCLUSIONS: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.


Assuntos
Carcinoma/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias Pancreáticas/diagnóstico , Fatores Etários , Pesquisa Biomédica/métodos , Carcinoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Programas de Rastreamento/métodos , Neoplasias Pancreáticas/genética , Vigilância da População/métodos , Fatores de Risco
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