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1.
Cancer Cell ; 30(5): 806-821, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27846393

RESUMO

We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.


Assuntos
Metilação de DNA , Elementos Facilitadores Genéticos , Epigenômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma de Célula do Manto/genética , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Simulação por Computador , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição SOXC/genética
2.
Epigenomics ; 8(6): 801-16, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27323310

RESUMO

AIM: To characterize the genotypic and phenotypic extent of multilocus imprinting disturbances (MLID). MATERIALS & METHODS: We analyzed 37 patients with imprinting disorders (explorative cohort) for DNA methylation changes using the Infinium HumanMethylation450 BeadChip. For validation, three independent cohorts with imprinting disorders or cardinal features thereof were analyzed (84 patients with imprinting disorders, 52 with growth disorder, 81 with developmental delay). RESULTS: In the explorative cohort 21 individuals showed array-based MLID with each one displaying an Angelman or Temple syndrome phenotype, respectively. Epimutations in ZDBF2 and FAM50B were associated with severe MLID regarding number of affected regions. By targeted analysis we identified methylation changes of ZDBF2 and FAM50B also in the three validation cohorts. CONCLUSION: We corroborate epimutations in ZDBF2 and FAM50B as frequent changes in MLID whereas these rarely occur in other patients with cardinal features of imprinting disorders. Moreover, we show cell lineage specific differences in the genomic extent of FAM50B epimutation.


Assuntos
Metilação de DNA , Deficiências do Desenvolvimento/genética , Impressão Genômica , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fenótipo , Proteínas/genética , Análise de Sequência de DNA
3.
Genes Chromosomes Cancer ; 55(9): 677-87, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27121553

RESUMO

Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytogenetic analysis we detected a reciprocal translocation t(6;12)(q21;q24.3). By sequencing, the translocation was shown to form a fusion between the 5' region of ZCCHC8 and the 3' region of ROS1. RT-PCR analyses confirmed the existence of an in-frame fusion transcript with ZCCHC8 exons 1-3 joined to ROS1 exons 36-43. In addition to the ZCCHC8-ROS1 fusion, we detected a deletion in the short arm of chromosome 9, including homozygous loss of the CDKN2A/2B locus in 9p21.3 and heterozygous deletion of the HAUS6 gene in 9p22.1. The latter encodes a protein involved in faithful chromosome segregation by regulating microtubule nucleation and its deletion might be associated with the marked subclonal changes of ploidy observed in the tumor. This report adds the ZCCHC8-ROS1 fusion as oncogenic driver in GBM and supports the role of ROS1 activation in the pathogenesis of a subset of GBM. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 6/genética , Glioblastoma/congênito , Glioblastoma/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética/genética , Hibridização Genômica Comparativa , Análise Citogenética , Glioblastoma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Orphanet J Rare Dis ; 11: 44, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27101822

RESUMO

BACKGROUND: Fructose-1,6-bisphosphatase deficiency is a rare inborn error of metabolism affecting gluconeogenesis with only sporadic reports on its molecular genetic basis. RESULTS: We report our experience with mutation analysis in 14 patients (13 families) with fructose-1,6-bisphosphatase deficiency using conventional Sanger sequencing and multiplex ligation-dependent probe amplification analysis, and we provide a mutation update for the fructose bisphosphatase-1 gene (FBP1). Mutations were found on both chromosomes in all of our 14 patients including 5 novel mutations. Among the novel mutations is a 5412-bp deletion (c.-24-26_170 + 5192del) including the entire coding sequence of exon 2 of FBP1 that was repeatedly found in patients from Turkey and Armenia which may explain earlier poorly defined findings in patients from this area. This deletion can be detected with specific primers by generation of a junction fragment and by MLPA and SNP array assays. MLPA analysis was able to detect copy number variations in two further patients, one heterozygous for a deletion within exon 8, another heterozygous for a novel deletion of the entire FBP1 gene. CONCLUSIONS: Based on our update for the FBP1 gene, currently listing 35 mutations worldwide, and knowledge of PCR conditions that allow simple detection of a common FBP1 deletion in the Armenian and Turkish population, molecular genetic diagnosis has become easier in FBP1 deficiency. Furthermore, MLPA analysis may plays a useful role in patients with this disorder.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Deficiência de Frutose-1,6-Difosfatase/genética , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Éxons/genética , Humanos , Mutação , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Ligação a RNA
5.
Am J Med Genet A ; 170A(4): 1050-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26749249

RESUMO

Many chromosomal rearrangements that lead to copy-number gains or losses have been shown to cause distinctive and recognizable clinical phenotypes. Conventional cytogenetic analysis can detect many, but not all, rearrangements depending on its power of resolution. The wide use of whole-genome array-based comparative genomic hybridization (array-CGH) techniques has allowed the detection of novel syndromes and to establish genotype-phenotype correlations by delineating at high resolution the regions involved in specific chromosomal aberrations. We report on a two and half-year-old female patient with intellectual disability and distinctive phenotypic features resulting from a de novo duplication of about 0.3 Mb in 21q22.3 associated with duplication of about 0.3 Mb in 12p13.33. The patient's chromosomal abnormalities were identified at the cytogenetic molecular level, using SNP array analysis, while GTG banding technique revealed a normal karyotype. Clinical findings of the patient were compared with Down syndrome and 12p duplication syndrome. This study suggests that an area of contiguous genes on the distal part of chromosome 21 (21q22.3) contribute to the Down syndrome phenotype and indicates that genes in the distal region of 12p (12p13.33) account for many facial characteristics and hypotonia of trisomy 12p syndrome.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Estudos de Associação Genética , Fenótipo , Trissomia , Encéfalo/patologia , Pré-Escolar , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA , Facies , Feminino , Humanos , Cariotipagem , Imagem por Ressonância Magnética , Polimorfismo de Nucleotídeo Único
6.
Nat Genet ; 47(11): 1316-1325, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437030

RESUMO

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.


Assuntos
Linfoma de Burkitt/genética , Metilação de DNA , Linfoma Folicular/genética , Mutação , Transcriptoma/genética , Adolescente , Adulto , Idoso , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Centro Germinativo/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/genética , Translocação Genética , Adulto Jovem
7.
Eur J Hum Genet ; 23(10): 1334-40, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25604858

RESUMO

X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.


Assuntos
Cromossomos Humanos X/genética , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Ligação Genética/genética , Doença de Parkinson/genética , Adulto , Idoso , Mapeamento Cromossômico/métodos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Filipinas , Polimorfismo Genético/genética
8.
J Med Genet ; 51(6): 407-12, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24721835

RESUMO

BACKGROUND: In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare. PURPOSE/OBJECTIVE: We have investigated the clinical and molecular features of a familial DNA-methylation disorder. METHODS: Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed. RESULTS: In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene. CONCLUSIONS: The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.


Assuntos
Metilação de DNA/genética , Doenças Genéticas Inatas/genética , Alelos , Análise Mutacional de DNA , Epigenômica , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem
9.
Blood ; 123(8): 1187-98, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24398325

RESUMO

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.


Assuntos
Linfócitos B/fisiologia , Linfoma de Burkitt/classificação , Linfoma de Burkitt/genética , Genes myc/genética , Translocação Genética/genética , Adolescente , Adulto , Idoso , Linfoma de Burkitt/patologia , Linhagem Celular , Criança , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Gradação de Tumores , Recidiva , Adulto Jovem
10.
Genes Chromosomes Cancer ; 53(4): 309-16, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24446122

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either the TCL1 or MTCP1 gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations in JAK3 have been identified in other T-cell malignancies. Since JAK3 is essential for T-cell maturation, we analyzed a cohort of 32 T-PLL patients for mutational hot spots in the JAK3 gene using a step-wise screening approach. We identified 14 mutations in 11 of 32 patients (34%). The most frequently detected mutation in our cohort was M511I (seen in 57% of cases) previously described as an activating change in other T-cell malignancies. Three patients carried two mutations in JAK3. In two patients M511I and R657Q were simultaneously detected and in another patient V674F and V678L. In the latter case we could demonstrate that the mutations were on the same allele in cis. Protein modeling and homology analyses of mutations present in other members of the JAK family suggested that these mutations likely activate JAK3, possibly by disrupting the activation loop and the interface between N and C lobes, increasing the accessibility of the catalytic loop. In addition, four of the 21 patients lacking a JAK3 point mutation presented an aberrant karyotype involving the chromosomal band 19p13 harboring the JAK3 locus. The finding of recurrent activating JAK3 mutations in patients with T-PLL could enable the use of JAK3 inhibitors to treat patients with this unfavorable malignancy who otherwise have a very poor prognosis.


Assuntos
Cromossomos Humanos Par 14/genética , Janus Quinase 3/genética , Leucemia Prolinfocítica de Células T/genética , Idoso , Sequência de Aminoácidos , Estudos de Coortes , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação
11.
PLoS One ; 8(10): e75692, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24116068

RESUMO

The human hepatic cell line LX-2 has been described as tool to study mechanisms of hepatic fibrogenesis and the testing of antifibrotic compounds. It was originally generated by immortalisation with the Simian Vacuolating Virus 40 (SV40) transforming (T) antigen and subsequent propagation in low serum conditions. Although this immortalized line is used in an increasing number of studies, detailed genetic characterisation has been lacking. We here have performed genetic characterisation of the LX-2 cell line and established a single-locus short tandem repeat (STR) profile for the cell line and characterized the LX-2 karyotype by several cytogenetic and molecular cytogenetic techniques. Spectral karyotyping (SKY) revealed a complex karyotype with a set of aberrations consistently present in the metaphases analyses which might serve as cytogenetic markers. In addition, various subclonal and single cell aberrations were detected. Our study provides criteria for genetic authentication of LX-2 and offers insights into the genotype changes which might underlie part of its phenotypic features.


Assuntos
Linhagem Celular , Células Estreladas do Fígado/citologia , Cariótipo , Células Estreladas do Fígado/metabolismo , Humanos , Cariotipagem
13.
Bioinformatics ; 29(13): 1600-6, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23620359

RESUMO

MOTIVATION: Protocols to generate strand-specific transcriptomes with next-generation sequencing platforms have been used by the scientific community roughly since 2008. Strand-specific reads allow for detection of antisense events and a higher resolution of expression profiles enabling extension of current transcript annotations. However, applications making use of this strandedness information are still scarce. RESULTS: Here we present a tool (Janus), which focuses on the identification of transcriptional active regions in antisense orientation to known and novel transcribed elements of the genome. Janus can compare the antisense events of multiple samples and assigns scores to identify mutual expression of either transcript in a sense/antisense pair, which could hint to regulatory mechanisms. Janus is able to make use of single-nucleotide variant (SNV) and methylation data, if available, and reports the sense to antisense ratio of regions in the vicinity of the identified genetic and epigenetic variation. Janus interrogates positions of heterozygous SNVs to identify strand-specific allelic imbalance. AVAILABILITY: Janus is written in C/C++ and freely available at http://www.ikmb.uni-kiel.de/janus/janus.html under terms of GNU General Public License, for both, Linux and Windows 64×. Although the binaries will work without additional downloads, the software depends on bamtools (https://github.com/pezmaster31/bamtools) for compilation. A detailed tutorial section is included in the first section of the supplemental material and included as brief readme.txt in the tutorial archive. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , RNA Antissenso/biossíntese , Software , Linhagem Celular Transformada , Metilação de DNA , Variação Genética , Humanos
14.
Eur J Hum Genet ; 21(8): 838-43, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23232699

RESUMO

Various genes located at imprinted loci and regulated by epigenetic mechanisms are involved in the control of growth and differentiation. The broad phenotypic variability of imprinting disorders suggests that individuals with inborn errors of imprinting might remain undetected among patients born small for gestational age (SGA). We evaluated quantitative DNA methylation analysis at differentially methylated regions (DMRs) of 10 imprinted loci (PLAGL1, IGF2R DMR2, GRB10, H19 DMR, IGF2, MEG3, NDN, SNRPN, NESP, NESPAS) by bisulphite pyrosequencing in 98 patients born SGA and 50 controls. For IGF2R DMR2, methylation patterns of additional 47 parent pairs and one mother (95 individuals) of patients included in the SGA cohort were analyzed. In six out of 98 patients born SGA, we detected DNA methylation changes at single loci. In one child, the diagnosis of upd(14)mat syndrome owing to an epimutation of the MEG3 locus in 14q32 could be established. The remaining five patients showed hypomethylation at GRB10 (n=2), hypomethylation at the H19 3CTCF-binding site (n=1), hypermethylation at NDN (n=1) and hypermethylation at IGF2 (n=1). IGF2R DMR2 hypermethylation was detected in five patients, six parents of patients in the SGA cohort and two controls. We conclude that aberrant methylation at imprinted loci in children born SGA exists but seems to be rare if known imprinting syndromes are excluded. Further investigations on the physiological variations and the functional consequences of the detected aberrant methylation are necessary before final conclusions on the clinical impact can be drawn.


Assuntos
Metilação de DNA , Loci Gênicos/genética , Impressão Genômica/genética , Recém-Nascido Pequeno para a Idade Gestacional , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Saúde da Família , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Análise de Sequência de DNA , Síndrome
15.
Br J Haematol ; 157(6): 702-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22469134

RESUMO

Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) show constitutive activation of nuclear factor (NF)-κB. Several genetic lesions contribute to this deregulated NF-κB activity. Here, we analysed two further NF-κB regulators for genetic lesions, the inhibitory factor TRAF3 and the key signalling component of the alternative NF-κB pathway, MAP3K14 (NIK). Single nucleotide polymorphism (SNP) array analysis of cHL cell lines revealed a uniparental disomy of the long arm of chromosome 14 associated with a biallelic deletion of TRAF3 located on this chromosome in cell line U-HO1. Cloning of the deletion breakpoint showed a 123 371 bp deletion. No inactivating mutations of TRAF3 were found in six other cHL cell lines or in microdissected HRS cells from seven cHL. However, in primary cHL samples interphase cytogenetic analyses revealed signal patterns indicating monoallelic deletion of TRAF3 in 3/20 other cases. SNP array analysis revealed a gain of copy number for MAP3K14 in three cHL cell lines. Gains of MAP3K14 were detected in 5/16 cases of primary cHL. In conclusion, in rare instances, HRS cells harbour inactivating mutations of the TRAF3 gene and recurrently show gains of MAP3K14, indicating that more components of NF-κB signalling show genetic lesions in HRS cells than previously known.


Assuntos
Doença de Hodgkin/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Fator 3 Associado a Receptor de TNF/genética , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Criança , Análise Citogenética , Feminino , Deleção de Genes , Dosagem de Genes , Doença de Hodgkin/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transativadores/genética , Transativadores/metabolismo
16.
Int J Cancer ; 131(5): E830-5, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22213068

RESUMO

A single nucleotide polymorphism-chip analysis of 98 cases of aggressive B-cell lymphomas revealed a recurrent deletion at 19p13 in nine of the cases. Six further cases with deletions encompassing this region were found in array-comparative genomic hybridization data of 295 aggressive B-cell lymphomas from a previous study. Three cases even showed a homozygous deletion, suggesting a tumor suppressor gene in the deleted region. Two genes encoding members of the tumor necrosis factor superfamily (TNFSF) were located in the minimally deleted region, that is, TNFSF7 and TNFSF9. As no mutations were found within the coding exons of the remaining alleles in the lymphomas with heterozygous deletions, we speculate that the deletions may mostly function through a haploinsufficiency mechanism. The cases with deletions encompassed both diffuse large B-cell lymphomas and Burkitt lymphomas, and a deletion was also found in a Hodgkin lymphoma cell line. Thus, TNFSF7 and TNFSF9 deletions are recurrent genetic lesions in multiple types of human lymphomas.


Assuntos
Ligante 4-1BB/genética , Linfoma de Burkitt/genética , Ligante CD27/genética , Cromossomos Humanos Par 19/genética , Deleção de Genes , Linfoma Difuso de Grandes Células B/genética , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , DNA de Neoplasias/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único
17.
Eur J Med Genet ; 54(5): e501-4, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21700002

RESUMO

We describe a 3.5 year old girl presenting with short stature, developmental delay, marked muscular hypotonia with ataxia, premature pubarche, and dysmorphic features. A 1.07-1.12Mb-sized de novo microdeletion of chromosome 19p13.11 is most likely the cause for the clinical phenotype. The patient did not show any abnormalities of the extremities which contrasts with the finding of one previously reported patient with an overlapping deletion presenting with split hand and foot malformation (SHFM). The remarkable difference is that in the previously described patient but not in the patient reported herein the genes EPS15L1 and CALR3 were deleted. As EPS15L1 has been associated with limb development previously, the presented case provides indirect evidence that this may be a new candidate gene for SHFM. A possible genotype-phenotype correlation is provided based on literature review and comparison of our patient to the previously reported patients with overlapping or partly overlapping copy number variations in 19p13.11.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Deformidades Congênitas dos Membros/genética , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Cariotipagem , Fenótipo
18.
PLoS One ; 6(4): e18436, 2011 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-21494621

RESUMO

ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.


Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/enzimologia , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Animais , Sequência de Bases , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Hospedeiro Imunocomprometido , Imunofenotipagem , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Indução de Remissão , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Hum Mutat ; 32(1): 98-106, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21120951

RESUMO

Next-generation sequencing and the availability of high-density genotyping arrays have facilitated an analysis of somatic and meiotic mutations at unprecedented level, but drawing sensible conclusions about the functional relevance of the detected variants still remains a formidable challenge. In this context, the study of allelic imbalance in intermediate RNA phenotypes may prove a useful means to elucidate the likely effects of DNA variants of unknown significance. We developed a statistical framework for the assessment of allelic imbalance in next-generation transcriptome sequencing (RNA-seq) data that requires neither an expression reference nor the underlying nuclear genotype(s), and that allows for allele miscalls. Using extensive simulation as well as publicly available whole-transcriptome data from European-descent individuals in HapMap, we explored the power of our approach in terms of both genotype inference and allelic imbalance assessment under a wide range of practically relevant scenarios. In so doing, we verified a superior performance of our methodology, particularly at low sequencing coverage, compared to the more simplistic approach of completely ignoring allele miscalls. Because the proposed framework can be used to assess somatic mutations and allelic imbalance in one and the same set of RNA-seq data, it will be particularly useful for the analysis of somatic genetic variation in cancer studies.


Assuntos
Desequilíbrio Alélico/genética , Transcriptoma , Interpretação Estatística de Dados , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
20.
Haematologica ; 95(12): 2047-55, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20823134

RESUMO

BACKGROUND: Knowledge about the genetic lesions that occur in Burkitt's lymphoma, besides the pathognomonic IG-MYC translocations, is limited. DESIGN AND METHODS: Thirty-nine molecularly-defined Burkitt's lymphomas were analyzed with high-resolution single-nucleotide polymorphism chips for genomic imbalances and uniparental disomy. Imbalances were correlated to expression profiles and selected micro-RNA analysis. Translocations affecting the MYC locus were studied by fluorescence in situ hybridization. RESULTS: We detected 528 copy number changes, defining 29 recurrently imbalanced regions. Five hundred and eighteen regions of uniparental disomy were found, but these were rarely recurrent. Combined imbalance mapping and expression profiling revealed a strong correlation between copy number and expression. Several recurrent imbalances affected the MYC pathway: the micro-RNA-supercluster 17-92 was frequently gained and the transcription factor E2F2 was recurrently deleted. Molecular Burkitt's lymphoma lacking MYC translocations showed MYC gains. Amplifications of the polymerase iota gene were associated with increased frequency of positions scored as aberrant. CONCLUSIONS: The present findings suggest that uniparental disomies do not play a major role in the pathogenesis of Burkitt's lymphoma, whereas some genes may contribute to the development of this lymphoma through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic alterations in Burkitt's lymphoma. The pattern and rarity of chromosomal changes detectable, even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support the hypothesis that deregulation of the MYC pathway is the major force driving the pathogenesis of Burkitt's lymphoma, but show that this deregulation is more complex than previously known.


Assuntos
Linfoma de Burkitt/genética , Aberrações Cromossômicas , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Polimorfismo de Nucleotídeo Único , Linfoma de Burkitt/patologia , Fator de Transcrição E2F2/genética , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Genes de Imunoglobulinas/genética , Genoma Humano/genética , Genótipo , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Dissomia Uniparental
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