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1.
Gene ; 715: 143957, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276734

RESUMO

MPIG6B has orthologous physiological effects in human and mice, which regulates platelet production and function. For this reason, germline loss-of-function mutations in this gene cause congenital thrombocytopenia that is associated with bone marrow fibrosis, organomegaly and subsequent anemia. This was described in a consanguineous Arabian family with a novel truncation mutation (p.C108*) in chromosome 6, open reading frame 25 gene, also known as MPIG6B. In our case, we identified a homozygous frameshift variation (c.392delC,p.P134Lfs*10) in a ten-month-old boy presenting with signs of pallor, splenomegaly and resistant hemocytopenia. Interestingly, this is a new form of a MPIG6B variation, which could disrupt the effector protein for the key hematopoiesis regulators. This report adds to the growing number of mutations causing complex clinical manifestations associated with pancytopenia and splenomegaly in children.


Assuntos
Cromossomos Humanos Par 6/genética , Mutação da Fase de Leitura , Fases de Leitura Aberta , Pancitopenia/genética , Esplenomegalia/genética , Grupo com Ancestrais do Continente Asiático , Humanos , Lactente , Masculino , Pancitopenia/patologia , Esplenomegalia/patologia
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 682-685, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302910

RESUMO

OBJECTIVE: To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. METHODS: Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. RESULTS: Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. CONCLUSION: The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.


Assuntos
Diagnóstico Pré-Natal , Translocação Genética , Síndrome de Wolf-Hirschhorn/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Linhagem , Gravidez
3.
Anticancer Res ; 39(6): 2861-2869, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177124

RESUMO

BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis. MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization. RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls. CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.


Assuntos
Arildialquilfosfatase/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Aberrações Cromossômicas , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade
4.
BMC Med Genet ; 20(1): 72, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053115

RESUMO

BACKGROUND: Genome wide association study (GWAS) has become the major means to screen for the genetic variants associated with risk and prognosis of different diseases. A recent GWAS has discovered three novel intronic single nucleotide polymorphisms in genes LRFN2 (rs2494938), DNAH11 (rs2285947) and PLCXD2 (rs2399395) that are associated with altered risk of esophageal squamous cell carcinoma (ESCC) among Han Chinese populations. However, the prognostic significance of these variations in ESCC remains unclear. METHODS: To investigate the association of three novel single nucleotide polymorphisms (rs2494938, rs2285947, rs2399395) with the prognosis of ESCC patients, we recruited 287 ESCC patients treated with surgical resection and evaluated the potential significance of the three polymorphisms through Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards regression models. RESULTS: The ESCC patients carrying genotype AA at rs2494938 had worse survival and genotype GG at 2285947 had better prognosis (Log-rank P = 0.003 and Log-rank P = 0.037, respectively). In addition, rs2494938 at 6p21.1 was independently associated with overall survival of ESCC patients in recessive model [AA vs. GG/GA, HR = 3.12, 95% CI = 1.43-6.83, P = 0.004], rs2285947 at 7p15.3 was independently associated with overall survival of ESCC patients in both dominant model [AA/GA vs. GG, HR = 1.59, 95% CI = 1.02-2.49, P = 0.042] and additive model [AA vs. GA vs. GG, HR = 1.45, 95% CI = 1.05-2.01, P = 0.025]. CONCLUSIONS: This study demonstrated that the polymorphisms rs2494938 at 6p21.1 and rs2285947 at 7p15.3 may serve as independent prognostic biomarkers for ESCC, implying the potential biological role of their related genes (LRFN2 and DNAH11) in the process of ESCC development.


Assuntos
Dineínas do Axonema/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Íntrons , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Biomarcadores Tumorais/genética , China , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 7 , Carcinoma de Células Escamosas do Esôfago/patologia , Grupos Étnicos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
5.
Nat Commun ; 10(1): 1653, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971697

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células Dendríticas/patologia , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Proliferação de Células/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Humanos , Células Jurkat , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação Genética/genética , Irradiação Corporal Total
6.
Neuropathology ; 39(2): 97-105, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30856298

RESUMO

Subependymomas of the spinal cord are rare, do not often involve multiple levels, and very rarely recur. Here, we present a series of spinal cord subependymomas with a detailed description of the clinical, radiological and pathological features, and characterization by chromosomal microarray analysis. Briefly, the four patients included two men and two women, between the ages of 22 and 48 years. The most common presenting symptoms were neck and arm pain with upper extremity weakness. By imaging, the tumors were found to involve multiple spinal levels, including cervical/ cervico-thoracic (three patients) and thoracic (one patient), were all eccentric, and had minimal to no post-contrast enhancement. Two patients underwent gross total resection, one had a sub-total resection, and one underwent biopsy alone with a decompressive laminectomy. Follow up ranged from 6 months to 22 years. One patient (case 4) had recurrence 15 years following gross total resection and chromosomal microarray analysis revealed deletions on the long arm of chromosome 6. Our limited series suggests that spinal cord subependymomas can rarely recur, even following gross total resection, suggesting a possible role for long-term surveillance for these rare tumors.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Glioma Subependimal/genética , Glioma Subependimal/patologia , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/patologia , Adulto , Feminino , Deleção de Genes , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
7.
Morphologie ; 103(341 Pt 2): 116-121, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30885456

RESUMO

The 6p terminal deletions are rare and usually early diagnosed because of their association with eye and cranio-facial anomalies, particularly as part of Axenfeld-Rieger syndrome in relation with the haploinsufficiency of FOXC1 gene. Deletions in the 22q11 region are frequent, highly correlated with DiGeorge syndrome also named CATCH22, and may be associated with many clinical features of various severities. We report a 31-year-old man with an unbalanced 45,XY,der(6)t(6;22)(p25;q11.2),-22 karyotype leading to monosomies in both 6p25 and 22q11 regions, confirmed by FISH and array-CGH. The length of the deletions was respectively 770 Kb for 6pter and 2.9 Mb for 22q11. This karyotype was discovered at adult age following problems of fertility. The chromosomal formula was unexpected, regarding the patient's medical history and clinical features. This case makes a great example of the difficulties to correlate genotype and phenotype, and furthermore demonstrates the complexity of genetic counselling even in a case with two different chromosomal unbalances.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 6/genética , Fenótipo , Translocação Genética , Adulto , Humanos , Infertilidade Masculina/genética , Cariotipagem , Masculino
8.
Mol Genet Genomic Med ; 7(3): e553, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30693664

RESUMO

BACKGROUND: Several genome-wide association studies already explored the associations between 6q25.1 rs2046210 polymorphism and breast cancer (BC), but the results of these studies were not consistent. Thus, we conducted a meta-analysis of relevant studies to better analyze the effects of rs2046210 polymorphism on individual susceptibility to BC. METHODS: PubMed, Web of Science, and Embase were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Totally 21 studies with 261,703 subjects were analyzed. A significant association with BC was observed for the rs2046210 polymorphism in GG versus GA +AA (dominant comparison, p < 0.0001, OR = 0.78, 95% CI 0.73-0.83), AA versus GG + GA (recessive comparison, p < 0.0001, OR = 1.21, 95% CI 1.18-1.24), GA versus GG + AA (overdominant comparison, p < 0.0001, OR = 1.12, 95% CI 1.08-1.16), and G versus A (allele comparison, p < 0.0001, OR = 0.86, 95% CI 0.82-0.89). Further subgroup analyses yielded similar positive results in both Asians and Caucasians. CONCLUSION: In summary, our findings suggested that the rs2046210 polymorphism may serve as a potential genetic biomarker of BC in both Asians and Caucasians.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Polimorfismo Genético , Feminino , Humanos
9.
Breast Cancer Res ; 21(1): 3, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642363

RESUMO

BACKGROUND: Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas. METHODS: We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach. RESULTS: We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017). CONCLUSION: Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Idoso , Mama , Estudos de Casos e Controles , Mapeamento Cromossômico , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
11.
Schizophr Bull ; 45(1): 222-232, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29474680

RESUMO

Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness.


Assuntos
Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença/genética , Substância Cinzenta/patologia , Lobo Parietal/patologia , Córtex Pré-Frontal/patologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/patologia , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Feminino , Estudos de Associação Genética , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Parietal/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Risco , Esquizofrenia/diagnóstico por imagem , Adulto Jovem
12.
Eur J Med Genet ; 62(6): 103531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30142436

RESUMO

Interstitial deletions involving chromosome region 6p21.31p21.2 have not been previously reported in the literature. Here, we present a 2 year old girl with global developmental delay, severe speech delay, dysmorphic features, laryngeal cleft, anterior descending aorta that occluded the left main bronchus and a novel de novo deletion of chromosome 6: arr[hg19] 6p21.31p21.2 (35462950-36725083)x1. The deletion, which was diagnosed by array comparative genomic hybridization and further confirmed with fluorescence in situ hybridization, was approximately 1.26 Mb and contained 28 RefSeq genes. The deleted region includes 24 protein coding genes and 4 non-coding genes. This represents a novel microdeletion that has not been previously reported in the literature.


Assuntos
Aorta Torácica/anormalidades , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 6/genética , Anormalidades Congênitas/genética , Deficiências do Desenvolvimento/genética , Laringe/anormalidades , Pré-Escolar , Transtornos Cromossômicos/patologia , Anormalidades Congênitas/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Laringe/patologia , Síndrome
13.
Hematol Oncol Stem Cell Ther ; 12(1): 26-31, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30336122

RESUMO

OBJECTIVE/BACKGROUND: Chronic lymphocytic leukemia is one of the commonest leukemias affecting adults. CD39 inhibits T-cell and Natural killer (NK) cell responses by hydrolyzing adenosine triphosphate and adenosine diphosphate, suppressing the immune system. We investigated expression of CD39 on CD4+ T Lymphocytes in chronic lymphocytic leukemia (CLL) patients and its relationship with deletion 6q, its association with disease stage and survival. METHODS: Thirty CLL patients and 20 matched controls were included in the study. Bone marrow studies with immunophenotyping, CD39, CD38, and ZAP-70, and detection of del 6q by FISH were performed. RESULTS: CD39+ CD4+ T helper cells in CLL patients were significantly expressed compared with the controls (p < .001). Levels of CD39+ CD4+ T cells were significantly expressed in high risk CLL patients. Del 6q was detected in 63.3% of patients and it correlated with CD39, CD38, and ZAP-70, and advanced stage disease. There was a significant relation between response to treatment and CD39 expression and del 6q, also there was a significant difference in overall survival (OS) between patients with and without Del 6q. CONCLUSION: CD39 expression on CD4+ Tcells and del 6q act as prognostic markers in CLL. Blocking or inhibition of CD39 may be a target for new immune therapy for CLL.


Assuntos
Apirase , Linfócitos T CD4-Positivos/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B , Proteínas de Neoplasias/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Apirase/biossíntese , Apirase/genética , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estudos Prospectivos
14.
Infect Genet Evol ; 67: 112-120, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30336268

RESUMO

BACKGROUND: TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients. METHODS: A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2). RESULTS: Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively). CONCLUSIONS: Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.


Assuntos
Cromossomos Humanos Par 6 , Coinfecção , Variação Genética , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Adulto , Alelos , Biomarcadores , Biópsia , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Desequilíbrio de Ligação , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Masculino , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
15.
Int J Cancer ; 145(1): 154-163, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561001

RESUMO

Previous a genome-wide association study (GWAS) of colorectal cancer in Japanese population has identified a risk region at the chromosome 6q26-q27 associated with colorectal cancer risk. However, the causal gene at this locus remained unclear. In our study, we enrolled a total of 14 candidate functional single nucleotide polymorphisms (SNPs) at 6q26-q27 (318 kb), and then genotyped them by TaqMan method in a Chinese population including 1,147 colorectal cancer cases and 1,203 controls. Among that, 5 SNPs were identified statistical association with colorectal cancer risk by logistic regression analysis. Of which, SNP rs420038 G > A in SLC22A3 was related to decreased risk of colorectal cancer (adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.67-0.94, p = 0.007), and also associated with lower expression of SLC22A3 (p = 0.040) using expression quantitative trait loci (eQTL) analysis. Moreover, by the luciferase assays, we found that compared to the G allele of rs420038, the A allele could suppress the activity of the promoter in SLC22A3. Furthermore, the expression of SLC22A3 was significantly higher in colorectal cancer tissues than that in paired normal tissues (p < 0.001). Meanwhile, the phenotypes of proliferation, migration, invasion, cell cycle and apoptosis of colorectal cancer cell were significantly affected by SLC22A3 in vitro. Our results revealed a novel susceptible locus, rs420038 in SLC22A3, which may be involved in colorectal cancer development and progression.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Grupo com Ancestrais do Continente Asiático/genética , Morte Celular/genética , Proliferação de Células/genética , Cromossomos Humanos Par 6 , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Grupos Étnicos/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
Am J Hum Genet ; 104(1): 157-163, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583798

RESUMO

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Disfunção Erétil/etiologia , Disfunção Erétil/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipotálamo/patologia , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromossomos Humanos Par 6/genética , Simulação por Computador , Europa (Continente) , Humanos , Masculino , Proteínas Repressoras/genética
17.
Br J Haematol ; 184(3): 405-417, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30450575

RESUMO

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hipersensibilidade a Drogas/genética , Predisposição Genética para Doença , Variação Genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 6/genética , Feminino , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Humanos , Lactente , Masculino , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/genética
18.
Cancer Genet ; 230: 37-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30497985

RESUMO

OBJECTIVES: To identify and characterize constitutional chromosomal rearrangements that mimic recurrent genetic abnormalities in acute myeloid leukemia (AML). METHODS: Bone marrow and blood chromosome studies were reviewed to identify constitutional rearrangements that resemble those designated by the 2017 revised World Health Organization (WHO) "AML with recurrent genetic abnormalities". Mate-pair sequencing (MPseq) was performed on cases with constitutional chromosome mimics of recurrent AML abnormalities to further define the rearrangement breakpoints. RESULTS: Three cases with constitutional rearrangements were identified, including t(6;9)(p23;q34), inv(16)(p13.1q22), and t(9;22)(q34.1;q12.2). Two cases were bone marrow specimens being evaluated for hematologic neoplasms, while one case was a blood specimen being evaluated for primary ovarian insufficiency. MPseq provided high-resolution and precise rearrangement breakpoints, and resolved the atypical FISH results generated with each rearrangement. CONCLUSIONS: Our findings illustrate that constitutional rearrangements can mimic recurrent genetic abnormalities observed in AML, and we emphasize the importance of correlating genetic data with clinical and hematopathologic information.


Assuntos
Aberrações Cromossômicas , Rearranjo Gênico , Leucemia Mieloide Aguda/diagnóstico , Adulto , Medula Óssea/patologia , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 9/genética , Diagnóstico Diferencial , Feminino , Humanos , Cariotipagem/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade
19.
BMC Cancer ; 18(1): 1262, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558566

RESUMO

BACKGROUND: Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit. Primary orbital melanoma (POM) is exceedingly rare, with approximately 60 cases reported to date. Despite recent advances in our understanding of the genetics of primary uveal and conjunctival melanomas, this information is lacking for POM. METHODS: DNA was extracted from 12 POM tissues, with matched germline DNA (where available). MLPA was conducted to detect chromosomal alterations and Sanger sequencing used to identify point mutations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ), and other genes implicated in melanoma prognosis (EIF1AX, SF3B1). Immunohistochemistry was performed to analyse BAP1 nuclear expression. RESULTS: MLPA detected copy number alterations in chromosomes 1p, 3, 6 and 8. Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma. A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease. CONCLUSIONS: EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance. Further in depth analysis of this rare group using differing 'omic technologies will provide novel insights into tumour pathogenesis.


Assuntos
Fator de Iniciação 1 em Eucariotos/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Mutação , Neoplasias Orbitárias/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Análise de Sequência de DNA
20.
Prensa méd. argent ; 104(10): 478-488, dic 2018. fig
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1046959

RESUMO

Las inversiones son reordenamientos intracromosómicos originados por dos rupturas en un cromosoma seguidas de la reinserción del fragmento rotado en 180º. Dependiendo si involucra o no al centrómero pueden ser pericén tricas o paracéntricas. La incidencia es 0.09 a 0.49/1.000. Las inversiones son rearreglos estructurales aparentemente equilibrados, por lo que la mayoría de los individuos portadores tienen fenotipos normales y una minoría tienen fenotipos patológicos (probablemente por alteración en la secuencia de genes o variación en la función de éstos por efectos de cambio de posición). Se presentan tres casos de inversiones detectas por la técnica de Bandeo G y confirmadas por Hibridación In Situ Fluorescente (FISH). Caso 1: INVERSION PARACENTRICA FAMILIAR DEL CROMOSOMA 13 ASOCIADA A RETRASO MENTAL Y DISMORFIAS. El exhaustivo análisis del árbol genealógico y el estudio cromosómico al mayor número posible de individuos permitió confirmar la asociación inversión/fenotipo patológico en este grupo familiar. 13 de 17 miembros son portadores de inv(13)(q31q32)inh.ish inv(13)(q31q32) (wcp13+). Caso 2: INVERSION PARACENTRICA DEL CROMOSOMA 6 DE NOVO EN RECIEN NACIDO CON RETRASO MADURATIVO GLOBAL Y RETRASO DEL CRECIMIENTO INTRAUTERINO. En este caso no es posible adjudicar que, el fenotipo afectado se deba a la inversión. Cariotipo: 46,XY,add(6)(q21)dn.ish inv(6)(q21q27)(wcp6+). Caso 3: INVERSION PERICENTRICA DEL CROMOSOMA 12 EN OVODONANTE. Dicha inversión no parece tener efecto sobre el fenotipo, ya que es una paciente con coeficiente intelectual normal y no presenta malformaciones congénitas. Cariotipo: 46,XX,inv(12)(p12q14).ish inv(12) (p12q14)(wcp12+). Este reporte de casos muestra los tres fenotipos posibles de una inversión: patológico, dudoso y normal. Es el primer reporte de una inv(13) que confiera fenotipo patológico.


The inversions are intrachromosomal rearrangements which occur when a single chromosome undergoes two breaks and the region between it's rotates 180 degrees before rejoining. Depending on whether or not it include the centromere, they can be pericentric or paracentric. The incidence is 0.09 to 0.49/1,000. The inversions are apparently balanced structural rearrangements, so the most of the carrier individuals show normal phenotypes and a minority have pathological phenotypes (probably due to variation in their function due to changes in position). Three cases of inversions detected by the G Banding technique and confirmed by Fluorescence In Situ Hybridization (FISH) are presented. Case 1: FAMILIAL PARACENTRIC INVERSION OF CHROMOSOME 13 ASSOCIATED WITH MENTAL RETARDATION AND DISMORPHIA. The exhaustive analysis of the pedigree and the chromosomal study to the greatest possible number of individuals confirmed the inversion/pathological phenotype association in this family group. 13 of 17 members are carriers of inv(13)(q31q32)inh.ish inv(13)(q31q32)(wcp13+). Case 2: PARACENTRAL INVERSION DE NOVO OF CHROMOSOME 6 IN NEWBORN WITH GLOBAL MATURITY DELAY AND DELAY OF INTRAUTERINE GROWTH. In this case it is not possible to adjudge that, the affected phenotype is due to the inversion. Karyotype: 46,XY,add(6)(q21)dn.ish inv(6)(q21q27)(wcp6+). Case 3: PERICENTRIC INVERSION OF CHROMOSOME 12 IN OVODONANT. This inversion does not seem to have an effect on the phenotype, since it is a patient with normal IQ and does not present congenital malformations. Karyotype: 46,XX,inv(12)(p12q14).ish inv(12) (p12q14)(wcp12+). This case report shows the three possible phenotypes of an inversion: pathological, questionable and normal. It is the first report of an inv(13) that confers pathological phenotype. Key words: chromosomal inversion, G Banding, phenotype, structural rearrangement, fluorescence in situ hybridization.


Assuntos
Fenótipo , Rearranjo Gênico/genética , Bandeamento Cromossômico , Hibridização in Situ Fluorescente , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 13
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