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3.
Blood ; 135(3): 181-190, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31697802

RESUMO

The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an "advanced-stage signature" in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a "localized-stage signature" had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.

4.
Leukemia ; 34(2): 543-552, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31530861

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2-2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2-2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3-2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

5.
Virchows Arch ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863183

RESUMO

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.

6.
Virchows Arch ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781845

RESUMO

The major aim of Session 1 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop was to collect examples of cutaneous lymphomas, excluding mycosis fungoides/Sezary syndrome, as defined in the current WHO classification of tumours of the haemetopoietic and lymphoid tissues. Overall 42 cases were submitted. These were considered in four main categories: primary cutaneous B cell lymphomas (12 cases), primary cutaneous T cell lymphomas/lymphoproliferations with CD8+/cytotoxic phenotype (12 cases), primary cutaneous CD30-positive lymphoproliferative disorders (15 cases) and primary cutaneous T cell lymphomas/leukaemias with CD4+ phenotype (4 cases). Using these cases as examples, we were able to present the full spectrum of cutaneous lymphoproliferations (excluding mycosis fungoides/Sezary syndrome), including examples of rare, provisional and new entities as listed in the 2017 update of the WHO classification. The findings are summarized in this report with emphasis on differential diagnostic considerations and the importance of clinico-pathological correlation for final subtyping. In presenting these findings we hope to raise awareness of this enigmatic group of neoplasms and to further our understanding of these rare disease entities.

7.
Virchows Arch ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31773249

RESUMO

This paper summarizes two sessions of the workshop during the XIX meeting of the European Association for Haematopathology (EAHP) held in Edinburgh in September 2018 dedicated to lymphomas of the gastrointestinal tract. The first session focused on the clinical and pathological features of primary gastrointestinal T cell and NK-cell lymphoproliferative disorders. The distinction between precursor lesions (RCD type 2) and enteropathy-associated T cell lymphoma were stressed, including the discussion of new diagnostic markers for the identification of aberrant phenotypes. Indolent T cell lymphoproliferative disorders of the gastrointestinal tract cases showed phenotypic heterogeneity with novel molecular alterations in few cases, such as STAT3-JAK2 fusion. In addition, novel clonal markers of disease, such as AXL and JAK3 somatic variants support the neoplastic nature of NK-cell enteropathy. The session on gastrointestinal tract B cell lymphoproliferations was dedicated to B cell lymphoproliferative disorders that arise primarily in the gastrointestinal tract (i.e., duodenal-type follicular lymphoma) or preferentially involve the digestive tract, such as large B cell lymphoma with IRF4 translocation and mantle cell lymphoma (MCL), including diverse molecular subtypes (i.e., CCND3-positive MCL mimicking MALT lymphoma). Challenging cases of high-grade B cell lymphomas with complex genetic profiles demonstrated the usefulness of novel molecular diagnostic methods such as targeted NGS to identify high-risk genetic features with potential clinical impact.

8.
Virchows Arch ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758317

RESUMO

Two sessions in the workshop of the 19th meeting of the European Association for Haematopathology termed "challenging extranodal lymphoproliferations" and "extranodal non-site-specific lymphoproliferations", dealt with a series of heterogenous cases. These included lymphoproliferations of all cell lineages, from reactive lesions mimicking lymphomas through indolent lymphoid neoplasia and tumours with unclear biological behaviour to aggressive and transformed lymphomas. The themes addressed included cases with borderline features between hyperplastic and neoplastic lesions, the diagnostic spectrum of IgG4-related disease, T cell lymphoproliferations arising in extranodal sites with presumed indolent behaviour, diverse clinical presentations of intravascular large B cell lymphoma, diagnostic problems encountered with tumours displaying plasmablastic morphology, pitfalls concerning rare entities like adult T cell lymphoma/leukaemia (ATLL) and extranodal natural killer/T cell (NK/T) lymphomas, and unusual clinical presentations of various lymphomas. Altogether, within the frame of these two sessions, 75 cases remarkably differing in their clinical background, genetic features and overall need for a meticulous diagnostic approach were presented and discussed. In this paper, the salient points raised during the discussion of the cases, current diagnostic concepts and recommendations relevant to the diagnosis of these lymphoproliferations are described.

9.
Blood ; 134(24): 2159-2170, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31562134

RESUMO

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.

10.
Am J Hematol ; 94(11): 1208-1213, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31396979

RESUMO

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first-line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.

11.
Br J Haematol ; 187(5): 627-637, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407320

RESUMO

Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.

13.
Genome Med ; 11(1): 27, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039827

RESUMO

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Transcriptoma , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Aprendizado de Máquina
14.
J Telemed Telecare ; : 1357633X19840475, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31007131

RESUMO

INTRODUCTION: We describe the use of telepathology in countries with restricted resources using two diagnosis assistance systems (Isabel and Memem7) in addition to the diagnoses made by experts in pathology via the iPath-Network. METHODS: A total of 156 cases, largely from Afghanistan, were analysed; 18 cases had to be excluded because of poor image quality. RESULTS: Of the remaining 138 cases (100%), a responsible physician provided a tentative diagnosis for 61.6% of them. With a diagnosis from a consultant pathologist, it was then possible to make a definite diagnosis in 84.8% of cases on the basis of images taken from hematoxylin and eosin staining sections alone. The use of the diagnosis assistance systems resulted in an ordered list of differential diagnoses in 82.6% (IsabelHealth) and in 74.6% (Memem7) of cases, respectively. Adding morphological terminology reduced the list of possible diagnoses to 52.2% (72 cases, Memem7), but improved their quality. DISCUSSION: In summary, diagnosis assistance systems are promising approaches to provide physicians in countries with restricted resources with lists of probable differential diagnoses, thus increasing the plausibility of the diagnosis of the consultant pathologist.

15.
Inflamm Intest Dis ; 3(3): 125-137, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30820434

RESUMO

Background: Eight percent of the human genome consists of human endogenous retroviruses (HERV). These genetic elements are remnants of ancient retroviral germ-line infections. Altered HERV expression is associated with several chronic inflammatory diseases. A physiological role of the HERV-derived proteins syncytin-1 and -2 has been described for the integrity of the human placental cell layer in terms of maintaining feto-maternal tolerance. The aim of this project was to investigate HERV expression in Crohn's disease (CD) with a further focus on syncytins in the gut. Material and Methods: Seventy-four ileal and colonic tissue samples of CD patients and healthy controls have been investigated for mRNA expression of major HERV groups by a comprehensive microarray screening. The most prominent differences have been validated by qRT-PCR. Immunohistochemistry (IHC), Western Blot (WB) and qRT-PCR were performed for syncytin-1 and -2. Results: HERV microarray screening revealed a distinct expression profile in ileal and colonic tissue, as well as differential expression in CD compared to healthy controls. qRT-PCR validated differential expression of at least 3 HERV-groups in CD. qRT-PCR, IHC and WB showed a tissue-dependent diminished epithelial expression of syncytins in inflamed CD. Conclusion: For the first time, HERV expression has been comprehensively studied in the gut. Between CD and healthy controls we could show a tissue dependent differential HERV expression profile. Notably, we could show that syncytin-1 and -2 are expressed in the epithelial layer in ileal and colonic tissue samples, whereas their diminished tissue-dependent expression in inflamed CD might modulate inflammatory processes at the gut barrier.

16.
Blood ; 133(15): 1664-1676, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30782609

RESUMO

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.


Assuntos
Variações do Número de Cópias de DNA , Linfoma de Células T Periférico/genética , Oncogenes , Feminino , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T Periférico/classificação , Masculino , Mutação , Proteínas com Domínio T/genética
17.
Blood ; 133(9): 962-966, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30567752

RESUMO

The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG-MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC-negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKB as a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each ≥3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center-derived B-cell lymphomas like KMT2D or CREBBP An exception is GNA13, which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Burkitt/classificação , Linfoma de Burkitt/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Mutação , Adolescente , Adulto , Linfoma de Burkitt/patologia , Criança , Pré-Escolar , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Estudos Retrospectivos , Adulto Jovem
18.
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
19.
Br J Haematol ; 184(4): 616-624, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30095158

RESUMO

Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki-67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression-based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki-67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk-adapted prospective clinical trials in the future.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
20.
Br J Haematol ; 184(3): 373-383, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565652

RESUMO

Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Pontos de Checagem da Fase S do Ciclo Celular , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , RNA Longo não Codificante/genética , RNA Neoplásico/genética
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