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2.
Virchows Arch ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31975037

RESUMO

Mantle cell lymphoma (MCL) shows a clinical aggressiveness that varies from patient to patient. Despite major advances in outcomes with current immunochemotherapy, the future development of therapies requires risk stratification to tailor therapy intensity. Within the group of reference pathologists for the ongoing trials of the European MCL Network, we performed a round robin test on a tissue microarray to evaluate the reproducibility in assessing the biomarkers of outcome in MCL. Cytological subtype, Ki67-index and expression of p53 and SOX11 were evaluated on 20 diagnostic tumour samples by eight participating labs independently. We demonstrate that the assessment of the proliferation index by counting the Ki67 positive cells as well as assessment of SOX11 and p53 expression status is reproducible between labs. For the most established prognostic biomarker, Ki67, the intra-class correlation coefficient was very good when assessed as a continuous parameter (0.87). The agreement was lower when the values were analysed in a dichotomized way applying the commonly used cutoff of 30% (kappa = 0.65, complete concordance of all labs in 13/20 (65%)). Cases with discrepant results between labs in the dichotomized analysis showed mean values close to the cutoff of 30%. Centralised scoring and digital image analysis revealed results in line with the scores from individual labs. All cases in our cohort were additionally assessed for gene expression signatures and of TP53 gene alterations. Given the good reproducibility when guidelines of assessment are applied, the biomarker studied in this inter-laboratory test presents potential candidates to be enhanced for risk-stratification in the future clinical trials.

4.
J Exp Clin Cancer Res ; 38(1): 446, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676012

RESUMO

BACKGROUND: NOTCH1 gene mutations in mantle cell lymphoma (MCL) have been described in about 5-10% of cases and are associated with significantly shorter survival rates. The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target. METHODS: Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in NOTCH1-mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of Delta-like ligand 4 (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo. RESULTS: Notch1 expression can be effectively stimulated in NOTCH1-mutated Mino cells by DLL4, whereas in the NOTCH1-unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both, NOTCH1-mutated and -unmutated MCL lymph nodes. Treatment of NOTCH1-mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with NOTCH1/2 mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of NOTCH1-mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for NOTCH1-mutated cells as they did not occur in the NOTCH1-wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL. CONCLUSION: DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients.

5.
Nat Commun ; 10(1): 3615, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399598

RESUMO

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.


Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenômica , Predisposição Genética para Doença/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos B/metabolismo , Sequência de Bases , Cromatina/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição
6.
Histopathology ; 75(5): 704-714, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31173643

RESUMO

AIMS: Mantle cell lymphoma (MCL) is a heterogeneous disease with an aggressive behaviour in most cases, which is associated with expression of sex determining region-Y-box11 (SOX11). Experimental studies have shown that SOX11 expression is associated with an angiogenic switch characterised by increased expression of angiogenic-related signatures and vascularisation of murine tumours. However, the relationship between angiogenesis and SOX11 expression in primary tumours is not well understood. Therefore, the aim of this study was to evaluate the development of microvascular angiogenesis in primary MCL in relation to SOX11 expression and its potential prognostic value. METHODS AND RESULTS: Fifty-six patients diagnosed with MCL, 38 SOX11-positive and 18 SOX11-negative, were studied. The relative intratumoral microvascular area (MVA) and microvessel density (MVD) (number of intratumoral microvessels/µm2 ) were measured on CD34-stained slides using a computerised image analysis system. SOX11-positive MCL showed a significant higher microvascular development than negative tumours (median MVA = 14.5 × 10-3 versus 5.0 × 10-3 P < 0.001; median MVD = 18.6/µm2 versus 14.2/µm2 , P = 0.021). Analysing the MVA and MVD as continuous variables, a high MVD was associated with shorter overall survival (P = 0.004), and a similar tendency was observed for high MVA (P = 0.064). The microvascular development was not related to the Ki-67 proliferative index or 17p/TP53, 9p or 11q alterations. CONCLUSIONS: These findings suggest that SOX11 promotes an angiogenic phenotype in primary MCL, which may contribute to the more aggressive behaviour of these tumours.

8.
Blood ; 133(9): 940-951, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30538135

RESUMO

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.


Assuntos
Ciclina D2/genética , Ciclina D3/genética , Elementos Facilitadores Genéticos , Rearranjo Gênico , Cadeias Leves de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Idoso , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXC/genética , Translocação Genética
9.
J Clin Invest ; 128(9): 4132-4147, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29990311

RESUMO

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.


Assuntos
Ciclina D1/genética , Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Código das Histonas , Humanos , Modelos Biológicos , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética
10.
Nat Med ; 24(6): 868-880, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29785028

RESUMO

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.


Assuntos
Cromatina/metabolismo , Epigenômica , Leucemia Linfocítica Crônica de Células B/genética , Linfócitos B/metabolismo , Sequência de Bases , Estudos de Coortes , Humanos
11.
Blood ; 132(4): 413-422, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29769262

RESUMO

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A/ATM deletions, but the proportion with 17p/TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53/CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.


Assuntos
Biomarcadores Tumorais/genética , Leucemia/genética , Leucemia/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Mutação , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Genômica , Humanos , Leucemia/classificação , Linfoma de Célula do Manto/classificação , Masculino , Prognóstico , Taxa de Sobrevida
12.
Leuk Lymphoma ; 59(10): 2318-2326, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29115891

RESUMO

Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38high, ZAP-70high, CD49dhigh, +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages.


Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Tempo para o Tratamento/estatística & dados numéricos , Adulto Jovem
13.
Mod Pathol ; 31(2): 313-326, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28984304

RESUMO

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.


Assuntos
Rearranjo Gênico , Linfoma de Células B/patologia , Linfoma Folicular/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Linfoma de Células B/genética , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo
15.
Curr Oncol Rep ; 19(6): 43, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28466437

RESUMO

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm, incurable with current therapies. The t(11;14)(q13;q32) involving cyclin D1 is considered the first oncogenic hit found in virtually all MCLs. However, additional secondary genomic alterations are essential for complete transformation. MCLs are genetically very unstable with several genetic alterations associated with its high proliferative behavior involving several oncogenic pathways. Furthermore, SOX11 is overexpressed in the majority of conventional MCLs (cMCL), including cyclin D1-negative cases, but absent in non-nodal leukemic MCL with indolent clinical behavior (nnMCL). Recent data have revealed the potential oncogenic role of SOX11 in MCL biology, highlighting its implication in tumor aggressiveness and progression. This review addresses the implication of SOX11 overexpression and frequent genetic lesions, cooperating with cyclin D1 underlying the pathogenesis of this aggressive disease.


Assuntos
Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Fatores de Transcrição SOXC/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinogênese , Humanos , Imuno-Histoquímica , Linfoma de Célula do Manto/patologia
17.
Nat Commun ; 8: 14175, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28165464

RESUMO

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10-10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.


Assuntos
Formação de Anticorpos/genética , Cromossomos Humanos/genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Linfócitos B/imunologia , Linfócitos B/fisiologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
Histopathology ; 70(4): 595-621, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27775850

RESUMO

AIMS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLsn ) in a series of 240 cases of DLBCL not otherwise specified [DLBCLall (NOS) ], including DLBCLsn training set (n = 11) and validation set (n = 18), and DLBCLnon-sn (n = 211). METHODS AND RESULTS: In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)+ . The genomic profile showed gains(+) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-) of 6q26q27 (55%) and 9p21.3 (64%); and copy number neutral loss of heterozygosity (LOH) (acquired uniparental disomy, UPD) at 6p25.3p21.31 (36%). This profile is comparable to DLBCLNOS (GSE11318, n = 203.) and closer to non-GCB/activated B-cell-like subtype (ABC). Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCLsn (P < 0.001). Array results were verified successfully by fluorescence in situ hybridization (FISH) on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), -9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82-91% agreement. Minimal common regions included biologically relevant genes of MNDA (+1q23.1), RGS1 and RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 (BLIMP1) and PARK2 (-6q21q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1) and BCL2 (+18q21.33). Correlation between DNA copy number and protein immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-like tumour associated macrophages (TAMs) and CD8+ T lymphocytes that associated with higher genomic instability. The DLBCLsn validation set confirmed the clinicopathological characteristics, all FISH loci and immunohistochemistry (IHC) for RGS1. RGS1, one of the most frequently altered genes, was analysed by IHC in DLBCLall and high RGS1 expression associated with non-GCB, EBER+ and unfavourable overall survival (hazard ratio = 1.794; P = 0.016). CONCLUSIONS: DLBCLsn has a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCLall (NOS) .


Assuntos
Cromossomos Humanos Par 1/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas RGS/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Transcriptoma
19.
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
20.
Cell Rep ; 16(8): 2061-2067, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27524613

RESUMO

Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator de Transcrição RelA/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Linfócitos B/metabolismo , Linfócitos B/patologia , Sítios de Ligação , Linhagem Celular Tumoral , Cromatina/química , Cromatina/metabolismo , Mapeamento Cromossômico , Cromossomos Humanos Par 15 , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Razão de Chances , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Risco , Fator de Transcrição RelA/metabolismo
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