RESUMO
Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is an auto-inflammatory disease for which a genetic basis has been postulated. Nevertheless, in contrast to the other periodic fever syndromes, no candidate genes have yet been identified. By cloning, following long insert size paired-end sequencing, of a de novo chromosomal translocation t(10;17)(q11.2;p13) in a patient with typical PFAPA syndrome lacking mutations in genes associated with other periodic fever syndromes we identified SPAG7 as a candidate gene for PFAPA. SPAG7 protein is expressed in tissues affected by PFAPA and has been functionally linked to antiviral and inflammatory responses. Haploinsufficiency of SPAG7 due to a microdeletion at the translocation breakpoint leading to loss of exons 2-7 from one allele was associated with PFAPA in the index. Sequence analyses of SPAG7 in additional patients with PFAPA point to genetic heterogeneity or alternative mechanisms of SPAG7 deregulation, such as somatic or epigenetic changes.
Assuntos
Antígenos de Superfície/genética , Febre/genética , Estudos de Associação Genética , Doenças Linfáticas/genética , Faringite/genética , Estomatite Aftosa/genética , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Feminino , Haploinsuficiência , Humanos , Lactente , Cariotipagem , Masculino , Síndrome , Translocação GenéticaRESUMO
Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.
Assuntos
Sistema de Registros , Tumor Rabdoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Dactinomicina/administração & dosagem , Dactinomicina/efeitos adversos , Estudos de Viabilidade , Alemanha , Humanos , Lactente , Recém-Nascido , Infusões Intraventriculares , Comunicação Interdisciplinar , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Dosagem Radioterapêutica , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/mortalidade , Taxa de SobrevidaAssuntos
Carcinoma Papilar/patologia , Proteína SMARCB1/genética , Neoplasias da Medula Espinal/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/cirurgia , Humanos , Laminectomia , Masculino , Pessoa de Meia-Idade , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/cirurgia , Vértebras Torácicas , Resultado do TratamentoRESUMO
Mucosa-associated lymphoid tissue (MALT) lymphomas most frequently involve the gastrointestinal tract and are the most common subset of extranodal non-Hodgkin lymphoma (NHL). Here we describe overexpression of BCL10, a novel apoptotic signalling gene that encodes an amino-terminal caspase recruitment domain (CARD), in MALT lymphomas due to the recurrent t(1;14)(p22;q32). BCL10 cDNAs from t(1;14)-positive MALT tumours contained a variety of mutations, most resulting in truncations either in or carboxy terminal to the CARD. Wild-type BCL10 activated NF-kappaB but induced apoptosis of MCF7 and 293 cells. CARD-truncation mutants were unable to induce cell death or activate NF-kappaB, whereas mutants with C-terminal truncations retained NF-kappaB activation but did not induce apoptosis. Mutant BCL10 overexpression might have a twofold lymphomagenic effect: loss of BCL10 pro-apoptosis may confer a survival advantage to MALT B-cells, and constitutive NF-kappaB activation may provide both anti-apoptotic and proliferative signals mediated via its transcriptional targets.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Caspases/metabolismo , Linfoma de Zona Marginal Tipo Células B/genética , Proteínas de Neoplasias/genética , Sequência de Aminoácidos , Proteína 10 de Linfoma CCL de Células B , Sítios de Ligação , Northern Blotting , Morte Celular/genética , Linhagem Celular , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 14/genética , DNA/química , DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Dados de Sequência Molecular , Mutação , NF-kappa B/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Estrutura Terciária de Proteína , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Translocação Genética , Células Tumorais CultivadasRESUMO
Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).
Assuntos
Genes Supressores de Tumor/genética , Predisposição Genética para Doença/genética , Neoplasias Primárias Múltiplas/genética , Proteínas/genética , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor , Sequência de Aminoácidos , Domínio Catalítico , Cromossomos Humanos Par 16/genética , Clonagem Molecular , Mapeamento de Sequências Contíguas , Enzima Desubiquitinante CYLD , Éxons/genética , Feminino , Genes Dominantes/genética , Mutação em Linhagem Germinativa/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Dados de Sequência Molecular , Mutação/genética , Neoplasias Primárias Múltiplas/patologia , Polimorfismo Genético/genética , Proteínas/química , RNA Mensageiro/análise , RNA Mensageiro/genética , Homologia de Sequência de Aminoácidos , Sitios de Sequências Rotuladas , Neoplasias Cutâneas/patologia , Tioléster Hidrolases/química , Ubiquitina TiolesteraseRESUMO
BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.
Assuntos
Linfoma Difuso de Grandes Células B/patologia , Neoplasias Faríngeas/patologia , Antraciclinas/uso terapêutico , Linfócitos B/metabolismo , Linfócitos B/patologia , Proteínas de Ligação a DNA/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Fatores Reguladores de Interferon/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
OBJECTIVE: While several genes have been identified to cause Parkinson's disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. METHODS: Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD-causing genes and a genome-wide linkage analysis were performed. RESULTS: Late-onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. CONCLUSIONS: The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD.
Assuntos
Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Idade de Início , Idoso , Encéfalo/patologia , Análise Mutacional de DNA , Feminino , Alemanha , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.
Assuntos
Centrômero/genética , Metilação de DNA , Impressão Genômica , Síndrome de Silver-Russell/genética , Adolescente , Centrômero/metabolismo , Cromossomos Humanos Par 11/genética , Feminino , Regulação da Expressão Gênica , Humanos , Lactente , Masculino , Especificidade de Órgãos , FenótipoRESUMO
Patients with Wiedemann-Beckwith syndrome (WBS, MIM 130650), a congenital overgrowth syndrome, have a known increased tumor risk especially for embryonic tumors. WBS belongs to the "imprinting" syndromes caused by overexpression of IGF2 and/or loss of CDKN1C on chromosome 11p15.5. A 13-year-old boy with WBS developed a spitzoid malignant melanoma (Clark level V, Breslow index 4.8 mm) on the right cheek. Genetic analyses of the patient's blood showed hypermethylation at the H19 locus on chromosome 11p. The (epi)genetic changes of the WBS locus might have played a role in the pathogenesis of melanoma development.
Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Cromossomos Humanos Par 11/genética , Metilação de DNA/genética , Neoplasias Faciais/diagnóstico , Impressão Genômica/genética , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adolescente , Síndrome de Beckwith-Wiedemann/genética , Bochecha , Neoplasias Faciais/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Melanoma/genética , RNA Longo não Codificante , RNA não Traduzido/genética , Neoplasias Cutâneas/genéticaRESUMO
The COVID-19 pandemic has placed healthcare resources around the world under immense pressure. South Africa, given the condition of its healthcare system, is particularly vulnerable. There has been much discussion around rational healthcare utilisation, ranging from diagnostic testing and personal protective equipment to triage and appropriate use of ventilation strategies. There has, however, been little guidance around use of laboratory tests once COVID-19 positive patients have been admitted to hospital. We present a working guide to rational laboratory test use, specifically for COVID-19, among hospitalised patients, including the critically ill. The specific tests, the reasons for testing, their clinical usefulness, timing and frequency are addressed. We also provide a discussion around evidence for the use of these tests from a clinical perspective.
RESUMO
Letter by Gopalan et al. on article by Singh and Moodley (Singh JA, Moodley K. Critical care triaging in the shadow of COVID-19: Ethics considerations. S Afr Med J 2020;110(5):355-359. https://doi.org/10.7196/SAMJ.2020.v110i5.14778); and response by Singh and Moodley.
Assuntos
Infecções por Coronavirus , Cuidados Críticos , Pandemias , Pneumonia Viral , Saúde Pública , África Austral , Betacoronavirus , COVID-19 , Humanos , Alocação de Recursos , SARS-CoV-2 , África do SulRESUMO
BACKGROUND AND OBJECTIVES: The genes encoding the Fcgamma receptors (FcgammaR) IIIa and IIIb (FCGR3A and FCGR3B) are clustered on chromosome 1 band q23-24 and exhibit allelic polymorphism. We investigated the molecular basis of additional new FCGR3 genomic variation. MATERIALS AND METHODS: A segment shared by FCGR3A and FCGR3B containing the polymorphic nucleotide positions 141, 147, 227, 266, and 277 in exon 3 was cloned and sequenced from genomic DNA of 30 donors and 3 bacterial artificial chromosome (BAC) clones. A mixture consisting of isolated FCGR3B*2- and FCGR3A- plasmids was cloned and sequenced as well. Additionally, nucleotide databases were screened for clones with variant FCGR3 sequences. RESULTS: A total of 12 FCGR3 variants defined by the polymorphic positions were detected in whole blood genomic DNA from 23 of 24 FCGR3B*2 and/or FCGR3B*3 positive donors, the DNA from two of three BAC clones and in the DNA mixture of isolated FCGR3B*2- and FCGR3A- plasmids. CONCLUSION: Nucleotide exchanges of the variants were non-random and resulted from two alternative nucleotides present in one of the polymorphic position of the basic FCGR3 forms. Polymerase chain reaction (PCR) artefacts cannot be excluded as origin of new variants, but there is strong evidence that at least two variants are the result of a somatic recombination.
Assuntos
Cromossomos Humanos Par 1/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Recombinação Genética , Clonagem Molecular , Feminino , Proteínas Ligadas por GPI , Humanos , Masculino , Análise de Sequência de DNARESUMO
The survival outcome of patients suffering from gliomas is directly linked to the complete surgical resection of the tumour. To help the surgeons to delineate precisely the boundaries of the tumour, we developed an intraoperative positron probe with background noise rejection capability. The probe was designed to be directly coupled to the excision tool such that detection and removal of the radiolabelled tumours could be simultaneous. The device consists of two exchangeable detection heads composed of clear and plastic scintillating fibres. Each head is coupled to an optic fibre bundle that exports the scintillating light to a photodetection and processing electronic module placed outside the operative wound. The background rejection method is based on a real-time subtraction technique. The measured probe sensitivity for (18)F was 1.1 cps kBq(-1) ml(-1) for the small head and 3.4 cps kBq(-1) ml(-1) for the large head. The mean spatial resolution was 1.6 mm FWHM on the detector surface. The gamma-ray rejection efficiency measured by realistic brain phantom modelling of the surgical cavity was 99.4%. This phantom also demonstrated the ability of the probe to detect tumour discs as small as 5 mm in diameter (20 mg) for tumour-to-background ratios higher than 3:1 and with an acquisition time around 4 s at each scanning step. These results indicate that our detector could be a useful complement to existing techniques for the accurate excision of brain tumour tissue and more generally to improve the efficiency of radio-guided cancer surgery.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Aumento da Imagem/instrumentação , Tomografia por Emissão de Pósitrons/instrumentação , Cirurgia Assistida por Computador/instrumentação , Transdutores , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , Miniaturização , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Integração de SistemasRESUMO
The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IkappaB kinase (IKK) in vitro. The S525P mutation reduces IKKalpha- and tumor necrosis factor (TNF)alpha-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFalpha-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL.
Assuntos
Transformação Celular Viral , Quinase I-kappa B/fisiologia , Linfoma de Células B/genética , Mutação Puntual/genética , Proteínas Proto-Oncogênicas c-rel/genética , Sequência de Aminoácidos , Animais , Western Blotting , Galinhas , Ensaio de Desvio de Mobilidade Eletroforética , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Hibridização in Situ Fluorescente , Rim/metabolismo , Luciferases/metabolismo , Linfoma de Células B/metabolismo , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/metabolismo , Dados de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação , Regiões Promotoras Genéticas/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-rel/metabolismo , Homologia de Sequência de Aminoácidos , Baço/metabolismo , Baço/virologia , Ativação Transcricional , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Molecular genetic analysis adds important information for lymphoma biology and classification, but the latter is challenged by recent improvement of combined chemo-immunotherapy. In aggressive lymphoma, molecular profiling identifies risk groups with certain genetic background but still the International Prognostic Index (IPI) remains the most important clinically applicable predictor of outcome. In follicular lymphoma (FL), the importance of the meshwork of bystander cells becomes increasingly evident. As combined immuno-chemotherapy improved the prognosis of the patients, several clinical trials indicated that the FLIPI still efficiently discriminates patients at risk for transformation and relapse, although several mechanisms of transformation seem to exist. In mantle cell lymphoma it has been proven that pathogenesis and prognosis mainly depend on deregulation of the cell cycle. A reliable clinical risk score could be established.
Assuntos
Linfoma Folicular/patologia , Linfoma de Célula do Manto/patologia , Linfoma/patologia , Anticorpos Monoclonais/uso terapêutico , Ciclo Celular/genética , Humanos , Linfoma/genética , Linfoma/terapia , Linfoma Folicular/genética , Linfoma Folicular/terapia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Prognóstico , Fatores de RiscoRESUMO
Mediastinal large B-cell (MBL) and classical Hodgkin lymphoma (HL) have several pathogenic mechanisms in common. As we recently observed aberrant tyrosine kinase (TK) activities in HL, we now analysed also MBL for such activities. Indeed, MBL and HL were the only B-cell lymphomas where elevated cellular phospho-tyrosine contents were typical features. Three TKs, JAK2, RON and TIE1, not expressed in normal B cells, were each expressed in about 30% of MBL cases, and 75% of cases expressed at least one of the TKs. Among the intracellular pathways frequently triggered by TKs, the PI3K/AKT pathway was activated in about 40% of MBLs and essential for survival of MBL cell lines, whereas the RAF/mitogen-activated protein kinase pathway seemed to be inhibited. No activating mutations were detected in the three TKs in MBL cell lines and primary cases. RON and TIE1 were each also expressed in about 35% and JAK2 in about 53% of HL cases. JAK2 genomic gains are frequent in MBL and HL but we observed no strict correlation of JAK2 genomic status with JAK2 protein expression. In conclusion, aberrant TK activities are a further shared pathogenic mechanism of MBL and HL and may be interesting targets for therapeutic intervention.
Assuntos
Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , Linfoma de Células B/genética , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Tirosina Quinases/genética , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Doença de Hodgkin/classificação , Doença de Hodgkin/enzimologia , Humanos , Linfoma de Células B/classificação , Linfoma de Células B/enzimologia , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismoRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive lymphoma derived from mature T cells, which is, in most cases, characterized by the presence of an inv(14)(q11q32)/t(14;14)(q11;q32) and a characteristic pattern of secondary chromosomal aberrations. DNA microarray technology was employed to compare the transcriptomes of eight immunomagnetically purified CD3+ normal donor-derived peripheral blood cell samples, with five highly purified inv(14)/t(14;14)-positive T-PLL blood samples. Between the two experimental groups, 734 genes were identified as differentially expressed, including functionally important genes involved in lymphomagenesis, cell cycle regulation, apoptosis and DNA repair. Notably, the differentially expressed genes were found to be significantly enriched in genomic regions affected by recurrent chromosomal imbalances. Upregulated genes clustered on chromosome arms 6p and 8q, and downregulated genes on 6q, 8p, 10p, 11q and 18p. High-resolution copy-number determination using single nucleotide polymorphism chip technology in 12 inv(14)/t(14;14)-positive T-PLL including those analyzed for gene expression, refined chromosomal breakpoints as well as regions of imbalances. In conclusion, combined transcriptional and molecular cytogenetic profiling identified novel specific chromosomal loci and genes that are likely to be involved in disease progression and suggests a gene dosage effect as a pathogenic mechanism in T-PLL.
Assuntos
Inversão Cromossômica , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 14 , Perfilação da Expressão Gênica , Leucemia Prolinfocítica/genética , Leucemia de Células T/genética , Polimorfismo de Nucleotídeo Único , Apoptose , Complexo CD3/biossíntese , Aberrações Cromossômicas , Reparo do DNA , Progressão da Doença , Dosagem de Genes , Humanos , Análise de Sequência com Séries de OligonucleotídeosRESUMO
The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISH-proven BCL3 involvement were identified with the translocation partners being IGH (n=51), IGL (n=2), IGK (n=2) and a non-IG locus (n=1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.
Assuntos
Leucemia de Células B/genética , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Translocação Genética , Adulto , Idoso , Proteína 3 do Linfoma de Células B , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 19 , Análise Citogenética , Feminino , Rearranjo Gênico , Genes de Imunoglobulinas , Histocitoquímica , Humanos , Hibridização in Situ Fluorescente , Leucemia de Células B/classificação , Leucemia de Células B/patologia , Linfoma de Células B/classificação , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40-66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9-36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1-14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.