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1.
Mod Pathol ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822801

RESUMO

Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.

2.
Haematologica ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296581

RESUMO

SOX11 is a valuable marker to identify biologically and clinically relevant groups of mantle cell lymphoma such as cyclin D1 negative and leukemic non-nodal mantle cell lymphoma. We aimed to establish a sensitive in situ hybridization analysis of SOX11 mRNA allowing its quantification within the histopathological context and compare it with immunohistochemistry and RT-qPCR. Furthermore, TP53 status was correlated with SOX11 mRNA levels. Sixty-six cases were investigated; 58 conventional mantle cell lymphomas, including 6 cyclin D1 negative (46 classic, 12 blastoid) and 8 leukemic non-nodal mantle cell lymphomas. RNAscope was used for the in situ hybridization and the results scored as 0 to 4. Mantle cell lymphoma cases with SOX11 positivity by immunohistochemistry were positive by RNAscope but with different scores. RT-qPCR showed a good correlation with the median of the grouped scores but had a wide variation in individual cases. The SOX11 negative leukemic non-nodal mantle cell lymphomas were also negative by RNAscope. TP53 was mutated in 13/63 (21%) cases, including 5/7 (71%) leukemic non-nodal and 8/56 (14%) conventional mantle cell lymphoma. Interestingly, of the TP53 mutated cases, 9 were in the RNAscope negative/low SOX11 group (9/15; 60%) and 4 in the high SOX11 group (4/36; 11%) (p=.0007). In conclusion, RNAscope is a reliable method to evaluate SOX11 mRNA levels. This study demonstrates the broad range of SOX11 mRNA levels in mantle cell lymphoma. An important finding is the significant correlation of TP53 mutations with negative/low SOX11 mRNA level both in leukemic non-nodal and conventional mantle cell lymphoma.

3.
Virchows Arch ; 475(6): 795-798, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31317311

RESUMO

The traditional concept of unidirectional maturation of hematopoietic cells has been called into question due to the recognition of lineage plasticity, which is increasingly found also in the clonal evolution of hematopoietic and lymphoid malignancies. Here we present an unusual case of a patient with TP53-mutated chronic lymphocytic leukemia (CLL) treated with a PI3Kδ inhibitor evolving to clonally related Langerhans cell histiocytosis (LCH) with acquired BRAF V600E and STK11 mutations and loss of expression of PAX-5 and other examined B cell markers. In indolent B cell lymphoma, transformation to a more aggressive high-grade lymphoma occurs frequently during the course of disease and is thought to be caused by clonal evolution. Our case further supports the concept of significant lineage plasticity in lymphomas and raises the question of a potential role of novel pharmacologic agents in clonal evolution.


Assuntos
Evolução Clonal , Histiocitose de Células de Langerhans/patologia , Ilhotas Pancreáticas/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Pancreáticas/patologia , Feminino , Histiocitose de Células de Langerhans/genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade
4.
Leukemia ; 33(9): 2227-2240, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31197258

RESUMO

One of the hallmarks of B lymphoid malignancies is a B cell clone characterized by a unique footprint of clonal immunoglobulin (IG) gene rearrangements that serves as a diagnostic marker for clonality assessment. The EuroClonality/BIOMED-2 assay is currently the gold standard for analyzing IG heavy chain (IGH) and κ light chain (IGK) gene rearrangements of suspected B cell lymphomas. Here, the EuroClonality-NGS Working Group presents a multicentre technical feasibility study of a novel approach involving next-generation sequencing (NGS) of IGH and IGK loci rearrangements that is highly suitable for detecting IG gene rearrangements in frozen and formalin-fixed paraffin-embedded tissue specimens. By employing gene-specific primers for IGH and IGK amplifying smaller amplicon sizes in combination with deep sequencing technology, this NGS-based IG clonality analysis showed robust performance, even in DNA samples of suboptimal DNA integrity, and a high clinical sensitivity for the detection of clonal rearrangements. Bioinformatics analyses of the high-throughput sequencing data with ARResT/Interrogate, a platform developed within the EuroClonality-NGS Working Group, allowed accurate identification of clonotypes in both polyclonal cell populations and monoclonal lymphoproliferative disorders. This multicentre feasibility study is an important step towards implementation of NGS-based clonality assessment in clinical practice, which will eventually improve lymphoma diagnostics.

5.
Mod Pathol ; 32(8): 1123-1134, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30952970

RESUMO

Angioimmunoblastic T-cell lymphoma is a peripheral T-cell lymphoma derived from follicular T-helper cells. High-throughput genomic sequencing studies have shown that angioimmunoblastic T-cell lymphoma carries frequent mutations in RHOAG17V and IDH2R172 genes. The clinico-pathological features of angioimmunoblastic T-cell lymphoma cases with RHOAG17V mutations have been addressed; however, similar studies for IDH2 mutated cases are lacking. Therefore, the aim of the present study was to evaluate the pathological features of angioimmunoblastic T-cell lymphoma with IDH2 mutations. In order to identify cases with IDH2 mutations, 50 cases previously diagnosed as angioimmunoblastic T-cell lymphoma were subjected to next-generation sequencing analysis using a custom panel covering four genes frequently mutated in angioimmunoblastic T-cell lymphoma including DNMT3A, TET2, IDH2 and RHOA. All cases were analyzed for PD1, ICOS, CXCL13, CD10, BCL6, CD21, CD23 and EBER in situ hybridization. Mutational analysis recognized three groups. Group 1: IDH2R172 mutations were identified in 20 cases (40%). All cases carried RHOAG17V mutations. Group 2: RHOAG17V mutations without IDH2R172 mutation were identified in 16 cases (32%), and Group 3: 14 cases (28%) without RHOAG17V or IDH2R172 mutations. Morphologically, angioimmunoblastic T-cell lymphoma cases with IDH2R172 mutations were characterized by the presence of medium to large clear cells (p = 0.00001), and a follicular T-helper phenotype with the particular feature of strong CD10 (p = 0.0268) and CXCL13 expression (p = 0.0346). Interestingly, TET2 mutations were identified in 32 of 33 (97%) cases with IDH2R172 and/or RHOAG17V mutations whereas only 55% of angioimmunoblastic T-cell lymphoma cases wild-type for these two genes carried TET2 mutations (p = 0.0022). In contrast, DNMT3A mutations were found in 48% of the cases and were equally distributed in the three groups. In conclusion, our results support the results of gene expression profiling studies suggesting that IDH2R172 mutations define a unique subgroup within angioimmunoblastic T-cell lymphoma with strong follicular T-helper-like phenotype and characteristic morphological features.

6.
Carcinogenesis ; 40(2): 289-302, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30753335

RESUMO

Cancer treatment with adoptively transferred tumor-associated antigen-specific CD4+ T-helper cells is a promising immunotherapeutic approach. In the pancreatic cancer model RIP-Tag2, the intraperitoneal (i.p.) application of Tag-specific TH1 cells exhibited a profound antitumoral efficiency. We investigated, whether an intravenous (i.v.) application of Tag-TH1 cells induces an equivalent therapeutic effect. Adoptively transferred fluorescent Tag-TH1 cells revealed a pronounced homing to the tumors after either i.p. or i.v. transfer, and both routes induced an almost equivalent therapeutic effect as demonstrated by magnetic resonance imaging, blood glucose level course and histology. The i.v. administration of Tag-TH1 cells induced p16INK4-positive/Ki67-negative tumor senescence more efficiently than i.p. administration. Both routes replenish host CD4+ T cells by transferred T cells and recruitment of B and dendritic cells to the tumors while reducing CD8+ T cells and depleting macrophages. Both administration routes efficiently induced a similar antitumoral efficiency despite the pronounced senescence induction after i.v. administration. Thus, a combinatory i.v./i.p. injection of therapeutic cells might overcome limitations of the individual routes and improve therapeutic efficacy in solid tumors.


Assuntos
Antígenos de Neoplasias/imunologia , Senescência Celular/imunologia , Neoplasias/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Microambiente Tumoral/imunologia , Transferência Adotiva/métodos , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Camundongos , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia
8.
Am J Surg Pathol ; 43(1): 110-120, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211726

RESUMO

Primary mediastinal large B-cell lymphoma (PMBL) is a mature large B-cell lymphoma of putative thymic B-cell origin involving the mediastinum with younger age distribution and better prognosis than diffuse large B-cell lymphoma (DLBCL), not otherwise specified. Recently, based on gene expression profile analysis and morphologic findings, cases of PMBL without mediastinal involvement have been reported. In this study, we analyzed 3 cases of nodal DLBCL with morphologic features of PMBL presenting in submandibular or supraclavicular lymph nodes, in middle-aged to elderly patients, 2 of them without clinical or radiologic evidence of mediastinal involvement. The 3 patients presented with stage I/II disease and had excellent response to R-CHOP/R-EPOCH therapy. The 3 cases showed MAL expression and were positive for CD23 and/or CD30. All 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement. There was no rearrangement of CIITA or PDL1/PDL2. Reverse transcriptase-multiplex ligation-dependent probe amplification, a mRNA-based gene expression profile analysis revealed high probability of PMBL (87.6%, 98.7%, and 99%) in these 3 cases. Targeted next-generation sequencing analysis showed SOCS1 mutations in the 3 cases, and TNFAIP3 and XPO1 mutations in one, further supporting the diagnosis of PMBL. In conclusion, we report 3 cases of nodal PMBL, 2 of them without mediastinal mass, and expression of cyclin D1 due to copy number gains of CCND1 gene, a diagnostic pitfall with mantle cell lymphoma and DLBCL, not otherwise specified.


Assuntos
Ciclina D1/genética , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/patologia , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Feminino , Humanos , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma de Célula do Manto/diagnóstico , Masculino , Pessoa de Meia-Idade
10.
BMC Med Genet ; 19(1): 144, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111295

RESUMO

BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.


Assuntos
Carcinoma Verrucoso/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Humanos , Doenças Raras
11.
Ann Hematol ; 97(10): 1859-1868, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29947976

RESUMO

Development of diffuse large B-cell lymphoma in chronic lymphocytic leukemia, so-called Richter transformation (RT), occurs in 2-5% of patients and is associated with poor outcome. The clinical features of RT are fairly non-specific and unable to discriminate transformation from other mimics. In case of clinically suspected RT, a CT/MRT is recommended, and FDG-PET/CT may help to select the site of biopsy. Radiological features suggestive of RT have been defined, but there are only limited data about their predictive value, and histological confirmation is still considered the gold standard for RT diagnosis. We retrospectively analyzed 34 patients with clinically suspected RT and available radiological and histological data. A histopathological diagnosis of RT with concordant clinical and radiological findings was obtained in 13 patients. In 18 patients, CT did not show features of transformation, concordant with lack of RT in the biopsy. Of interest, a distinct lymphoma other than DLBCL was identified in two of these cases. A false-positive radiological diagnosis of RT was rendered in two patients, including a case of Herpes simplex virus lymphadenitis. In conclusion, our findings confirm the central role of tissue biopsy in the diagnostic work up in case of clinically suspected RT.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Ciclo Celular , Progressão da Doença , Feminino , Humanos , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/genética , Masculino , Pessoa de Meia-Idade , Mutação , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Fatores de Risco , Transdução de Sinais , Tomografia Computadorizada por Raios X
12.
Cancers (Basel) ; 10(4)2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29617304

RESUMO

Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.

13.
Int J Cancer ; 142(3): 573-583, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28944451

RESUMO

Ionizing radiation is a well-recognized risk factor for the development of breast cancer. However, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and nonexposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n = 38) were subsequently validated in a second cohort (n = 39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p, was associated with radiation exposure. As TRPS1 overexpression is common in sporadic breast cancer, its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterized in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, while the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Acidente Nuclear de Chernobyl , Proteínas de Ligação a DNA/biossíntese , MicroRNAs/biossíntese , Neoplasias Induzidas por Radiação/metabolismo , Fatores de Transcrição/biossíntese , Adulto , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/genética , Inclusão em Parafina , Fatores de Transcrição/genética
14.
Virchows Arch ; 471(3): 347-353, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28589387

RESUMO

We present a rare case of non-invasive papillary urothelial carcinoma of the vagina as the initial presentation of a multicentric urothelial carcinoma also involving bladder and renal pelvis and report for the first time in the literature the molecular alterations observed in the vaginal urothelial lesion and the synchronous lesions of the urinary tract. In this case, the non-invasive papillary urothelial carcinoma in the vagina displayed the same genetic alterations in the FGFR3 and PIK3CA genes as those seen in the non-invasive papillary urothelial carcinoma of the bladder contrasting with the wild phenotype observed in the invasive urothelial carcinoma of the renal pelvis. This observation could reinforce the theory of "seeding" of carcinoma cells as a valid and most likely explanation of this multifocality. In addition, we emphasize in this report the importance of recognizing this rare lesion in the female genital tract and its differential diagnosis.


Assuntos
Carcinoma Papilar/patologia , Carcinoma de Células de Transição/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias Vaginais/patologia , Idoso , Carcinoma Papilar/genética , Carcinoma de Células de Transição/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Humanos , Pelve Renal/patologia , Neoplasias Primárias Múltiplas/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias Vaginais/genética
15.
Lab Invest ; 97(9): 1095-1102, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28581487

RESUMO

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPß, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPß for the unusual phenotype of ALK+ ALCL cells, C/EBPß was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK- cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPß knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK- ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPß knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK- ALCL, suggesting an additional role of C/EBPß in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPß plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL.


Assuntos
Basigina/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Antígenos CD/análise , Antígenos CD/genética , Antígenos CD/metabolismo , Basigina/análise , Basigina/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Linfonodos/química , Linfonodos/metabolismo , Linfoma Anaplásico de Células Grandes/química , Proteínas de Fusão Oncogênica/genética
16.
Int J Clin Exp Pathol ; 8(9): 11809-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26617931

RESUMO

We present the case of a 72-year old female with a right cerebellar pilocytic astrocytoma WHO grade I with an Isocitrate dehydrogenase 1 (IDH1) R132H mutation. The patient is recurrence-free 6 years after the initial diagnosis. Only one single case with strikingly similar clinicopathological features has been reported before. Otherwise, IDH1/2 mutations are not seen in pilocytic astrocytomas. The clinical implications of these findings are discussed.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Neoplasias Cerebelares/genética , Isocitrato Desidrogenase/genética , Mutação , Idoso , Astrocitoma/enzimologia , Astrocitoma/patologia , Astrocitoma/cirurgia , Neoplasias Cerebelares/enzimologia , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/cirurgia , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética , Resultado do Tratamento
17.
Front Biosci (Schol Ed) ; 7: 248-59, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25961700

RESUMO

The current classification of lymphoid neoplasms is based on the integrated utilisation of morphological, immunohistochemical, genetic and clinical criteria to define disease entities. Anaplastic large cell lymphoma is a paradigm for the identification of a disease entity based on morphological observations and immunophenotype, which paved the way for the subsequent discovery of the characteristic cytogenetic abnormality the translocation t(2;5)(p23;q35). In 1994, the t(2;5) was cloned and the NPM-ALK fusion gene generated by this rearrangement was identified. The year 2014 marked the 20th anniversary of this seminal publication by Steve Morris et al. The discovery of anaplastic lymphoma kinase (ALK) has allowed the definition of a distinct entity within the clinically and pathologically heterogeneous group of CD30+ lymphomas. The diagnosis of ALK-positive ALCL has become straightforward due to the generation of the reliable monoclonal antibody ALK-1 that also has led to the recognition of the histologic spectrum of the disease. ALK-positive ALCL has evolved in the last 20 years to an exciting model for signal transduction studies and targeted therapy.


Assuntos
Linfoma Anaplásico de Células Grandes/enzimologia , Receptores Proteína Tirosina Quinases/metabolismo , Quinase do Linfoma Anaplásico , Humanos , Linfoma Anaplásico de Células Grandes/genética , Receptores Proteína Tirosina Quinases/genética
18.
Br J Haematol ; 169(6): 795-803, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25819228

RESUMO

Recurrent mutations in MYD88 have been identified in >90% of lymphoplasmacytic lymphoma (LPL). Recently, WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis) syndrome-like mutations in CXCR4 have been described in 28% of LPL cases, and seem to impact clinical presentation and response to therapy. We investigated the presence of the MYD88 L265P mutation in 90 decalcified, formalin-fixed, paraffin-embedded (FFPE) bone marrow (BM) biopsies, including 51 cases of LPL, 14 cases of B-cell chronic lymphocytic leukaemia (CLL), 13 cases of marginal zone lymphoma (MZL) and 12 normal controls. In addition, the C-terminal domain of CXCR4 was sequenced in LPL cases. MYD88 L265P was found in 49/51 (96%) LPL cases and in 1/13 (7·6%) MZL (splenic type), whereas all CLL samples remained negative. The two MYD88 wild type LPL cases were associated with cold agglutinin disease. Mutations in CXCR4 were detected in 17/47 (36·2%) LPL cases, which showed a higher extent of BM infiltration and lower leucocyte counts (P = 0·02), haemoglobin (P = 0·05) and platelet counts (P = 0·01). In conclusion the detection of MYD88 L265P mutation in FFPE samples is reliable and useful for subtyping small B-cell lymphomas in BM biopsies. In addition, the presence of CXCR4 mutations identifies a subgroup of LPL patients with higher disease activity.


Assuntos
Mutação , Fator 88 de Diferenciação Mieloide/genética , Receptores CXCR4/genética , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Medula Óssea/patologia , Feminino , Humanos , Linfoma de Células B/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Sensibilidade e Especificidade
19.
PLoS One ; 10(2): e0117780, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25688981

RESUMO

Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBPß-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T-cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR-424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBPß, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL.


Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Linfoma Anaplásico de Células Grandes/imunologia , MicroRNAs/genética , Receptores Proteína Tirosina Quinases/metabolismo , Linfócitos T/metabolismo , Quinase do Linfoma Anaplásico , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , MicroRNAs/metabolismo , Receptores Proteína Tirosina Quinases/genética , Linfócitos T/imunologia
20.
PLoS One ; 8(5): e64544, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23741337

RESUMO

C/EBPß (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPß responsible for ALK-mediated oncogenesis. C/EBPß was knocked down in ALK+ ALCL cell lines with a C/EBPß-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPß. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPß was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPß-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPß in ALK-mediated oncogenesis.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas de Ciclo Celular/genética , RNA Helicases DEAD-box/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Anaplásico de Células Grandes/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína beta Intensificadora de Ligação a CCAAT/antagonistas & inibidores , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina , RNA Helicases DEAD-box/metabolismo , Perfilação da Expressão Gênica , Humanos , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Antígenos de Histocompatibilidade Menor , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Transcrição Genética
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