PubMed | Complutense University of Madrid, University of Oxford, Hospital Gregorio Maranon, University Pompeu Fabra and 5 more.
Type: | Journal: Nature communications | Year: 2016
Nuclear 3-end-polyadenylation is essential for the transport, stability and translation of virtually all eukaryotic mRNAs. Poly(A) tail extension can also occur in the cytoplasm, but the transcripts involved are incompletely understood, particularly in cancer. Here we identify a lineage-specific requirement of the cytoplasmic polyadenylation binding protein 4 (CPEB4) in malignant melanoma. CPEB4 is upregulated early in melanoma progression, as defined by computational and histological analyses. Melanoma cells are distinct from other tumour cell types in their dependency on CPEB4, not only to prevent mitotic aberrations, but to progress through G1/S cell cycle checkpoints. RNA immunoprecipitation, sequencing of bound transcripts and poly(A) length tests link the melanoma-specific functions of CPEB4 to signalling hubs specifically enriched in this disease. Essential in these CPEB4-controlled networks are the melanoma drivers MITF and RAB7A, a feature validated in clinical biopsies. These results provide new mechanistic links between cytoplasmic polyadenylation and lineage specification in melanoma.
Cascon A.,Hereditary Endocrine Cancer Group |
Cascon A.,Research Center Biomedica En Red Of Enfermedades Raras |
Comino-Mendez I.,Hereditary Endocrine Cancer Group |
Curras-Freixes M.,Hereditary Endocrine Cancer Group |
And 31 more authors.
Journal of the National Cancer Institute | Year: 2015
Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six-and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P =. 043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P =. 033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene. © 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com.
Comino-Mendez I.,Hereditary Endocrine Cancer Group |
Comino-Mendez I.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer |
Gracia-Aznarez F.J.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer |
Gracia-Aznarez F.J.,Human Genetics Group |
And 33 more authors.
Nature Genetics | Year: 2011
Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential. © 2011 Nature America, Inc. All rights reserved.
Martin-Perez D.,Lymphoma Group |
Sanchez E.,Hospital Nuestra Senora del Prado |
Maestre L.,Monoclonal Antibodies Unit |
Suela J.,Cytogenetics Unit |
And 6 more authors.
American Journal of Pathology | Year: 2010
Polycomb proteins are known to be of great importance in human cancer pathogenesis. SUZ12 is a component of the Polycomb PRC2 complex that, along with EZH2, is involved in embryonic stem cell differentiation. EZH2 plays an essential role in many cancer types, but an equivalent involvement of SUZ12 has not been as thoroughly demonstrated. Here we show that SUZ12 is anomalously expressed in human primary tumors, especially in mantle cell lymphoma (MCL), pulmonary carcinomas and melanoma, and is associated with gene locus amplification in some cases. Using MCL as a model, functional and genomic studies demonstrate that SUZ12 loss compromises cell viability, increases apoptosis, and targets genes involved in central oncogenic pathways associated with MCL pathogenesis. Our results support the hypothesis that the abnormal expression of SUZ12 accounts for some of the unexplained features of MCL, such as abnormal DNA repair and increased resistance to apoptosis. Copyright © American Society for Investigative Pathology.
Aggressive large B-cell lymphoma with plasma cell differentiation: Immunohistochemical characterization of plasmablastic lymphoma and diffuse large B-cell lymphoma with partial plasmablastic phenotype
Montes-Moreno S.,Lymphoma Group |
Gonzalez-Medina A.-R.,Hospital General Of Segovia |
Rodriguez-Pinilla S.-M.,Lymphoma Group |
Maestre L.,Monoclonal Antibodies Unit |
And 9 more authors.
Haematologica | Year: 2010
Background Plasmablastic lymphoma has recently come to be considered a distinct entity among mature B cell neoplasms, although the limits with diffuse large B-cell lymphoma (DLBCL) need to be more accurately defined. Design and Methods Here we show the results of an immunohistochemical study of 35 cases of plasmablastic lymphoma compared with a set of 111 conventional DLBCLs. Results Our results demonstrate that the use of a limited combination of immunohistochemical markers (PAX5&CD20, PRDM1/BLIMP1 and XBP1s) enables the identification of a plasmablastic immunophenotype highly characteristic of plasmablastic lymphoma cases and associated with an aggressive clinical behavior. Additionally, the study shows that the acquisition of a partial plasmablastic phenotype (PRDM1/BLIMP1 expression) in DLBCL is associated with shorter survival in R-CHOP-treated patients. Conclusions The use of a restricted combination of immunohistochemical markers (PAX5&CD20, PRDM1/BLIMP1 and XBP1s) enables a more accurate definition of terminal differentiation for large B-cell lymphoma. © 2010 Ferrata Storti Foundation.
Wahlin B.E.,Karolinska Institutet |
Aggarwal M.,Karolinska Institutet |
Aggarwal M.,Lymphoma Group |
Montes-Moreno S.,Lymphoma Group |
And 6 more authors.
Clinical Cancer Research | Year: 2010
Purpose: The microenvironment influences outcome in follicular lymphoma. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors. Experimental Design: Seventy follicular lymphoma patients with extreme clinical outcome ("poor" and "good" cases) were selected in a population-based cohort of 197. None of the 37 good-outcome patients died from lymphoma, whereas all the 33 poor-outcome patients succumbed in ≤5 years. Furthermore, the good-outcome patients were followed for a long time and needed no or little treatment. A tissue microarray was constructed from diagnostic, pretreatment biopsies. Cellular subsets were quantified after immunostaining, using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). Flow cytometry data from the same samples were also used. Results: Independently of the Follicular Lymphoma International Prognostic Index, CD4+ cells were associated with poor outcome and programmed death-1-positive and CD8+ cells were associated with good outcome. The prognostic values of CD4+ and programmed death-1-positive cells were accentuated when they were follicular and that of CD8+ cells were accentuated when they were interfollicular. Follicular FOXP3+ cells were associated with good outcome and interfollicular CD68+ cells were associated with poor outcome. Additionally, high CD4/CD8 and CD4 follicular/interfollicular ratios correlated with poor outcome. Conclusion: There are many important immune cell subsets in the microenvironment of follicular lymphoma. Each of these is independently associated with outcome. This is the first study showing the effect of the balance of the entire microenvironment, not only of individual subsets. ©2010 AACR.
Gomez-Abad C.,Lymphoma Group |
Pisonero H.,Lymphoma Group |
Pisonero H.,Hospital Universitario Marques Of Valdecilla |
Blanco-Aparicio C.,Experimental Therapeutics Programme |
And 11 more authors.
Blood | Year: 2011
PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4EBP1( Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. © 2011 by The American Society of Hematology.
Frenkel-Morgenstern M.,Spanish National Cancer Research Center |
Gorohovski A.,Spanish National Cancer Research Center |
Gorohovski A.,Kharkiv Polytechnic Institute |
Vucenovic D.,Spanish National Cancer Research Center |
And 3 more authors.
Nucleic Acids Research | Year: 2015
Chimeric RNAs that comprise two or more different transcripts have been identified in many cancers and among the Expressed Sequence Tags (ESTs) isolated from different organisms; they might represent functional proteins and produce different disease phenotypes. The ChiTaRS 2.1 database of chimeric transcripts and RNA-Seq data (http://chitars.bioinfo.cnio.es/) is the second version of the ChiTaRS database and includes improvements in content and functionality. Chimeras from eight organisms have been collated including novel sense-antisense (SAS) chimeras resulting from the slippage of the sense and anti-sense intragenic regions. The new database version collects more than 29 000 chimeric transcripts and indicates the expression and tissue specificity for 333 entries confirmed by RNA-seq reads mapping the chimeric junction sites. User interface allows for rapid and easy analysis of evolutionary conservation of fusions, literature references and experimental data supporting fusions in different organisms. More than 1428 cancer breakpoints have been automatically collected from public databases and manually verified to identify their correct cross-references, genomic sequences and junction sites. As a result, the ChiTaRS 2.1 collection of chimeras from eight organisms and human cancer breakpoints extends our understanding of the evolution of chimeric transcripts in eukaryotes as well as their functional role in carcinogenic processes. © The Author(s) 2014.
PubMed | Monoclonal Antibodies Unit and Spanish National Cancer Research Center
Type: Journal Article | Journal: Nucleic acids research | Year: 2015
Chimeric RNAs that comprise two or more different transcripts have been identified in many cancers and among the Expressed Sequence Tags (ESTs) isolated from different organisms; they might represent functional proteins and produce different disease phenotypes. The ChiTaRS 2.1 database of chimeric transcripts and RNA-Seq data (http://chitars.bioinfo.cnio.es/) is the second version of the ChiTaRS database and includes improvements in content and functionality. Chimeras from eight organisms have been collated including novel sense-antisense (SAS) chimeras resulting from the slippage of the sense and anti-sense intragenic regions. The new database version collects more than 29,000 chimeric transcripts and indicates the expression and tissue specificity for 333 entries confirmed by RNA-seq reads mapping the chimeric junction sites. User interface allows for rapid and easy analysis of evolutionary conservation of fusions, literature references and experimental data supporting fusions in different organisms. More than 1428 cancer breakpoints have been automatically collected from public databases and manually verified to identify their correct cross-references, genomic sequences and junction sites. As a result, the ChiTaRS 2.1 collection of chimeras from eight organisms and human cancer breakpoints extends our understanding of the evolution of chimeric transcripts in eukaryotes as well as their functional role in carcinogenic processes.
Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBCL not otherwise specified (NOS)
PubMed | Monoclonal Antibodies Unit, University of Barcelona, Tokai University and Anderson Cancer Center Madrid
Type: | Journal: Histopathology | Year: 2016
We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLIn 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)DLBCL