Alba Navarro

Publications (18)203.11 Total impact

• Article: Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features.

  Anna Enjuanes, Robert Albero, Guillem Clot, Alba Navarro, Sílvia Beà, Magda Pinyol, José I Martín-Subero, Wolfram Klapper, Louis M Staudt, Elaine S Jaffe, [......], Randy Gascoyne, Joseph M Connors, Dennis D Weisenburger, Timothy C Greiner, Wing-Chung Chan, Armando López-Guillermo, Andreas Rosenwald, German Ott, Elías Campo, Pedro Jares
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  ABSTRACT: Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behaviour characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n=132), MCL cell lines (n=6), and normal lymphoid tissue samples (n=31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations, and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations, and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 06/2013; · 5.44 Impact Factor
• Article: microRNA EXPRESSION PROFILES IDENTIFY SUBTYPES OF MANTLE CELL LYMPHOMA WITH DIFFERENT CLINICOBIOLOGICAL CHARACTERISTICS.

  Alba Navarro, Guillem Clot, Miriam Prieto, Cristina Royo, Maria Carmela Vegliante, Virginia Amador, Elena Hartmann, Itziar Salaverria, Silvia Beà, José Ignacio Martín-Subero, Andreas Rosenwald, German Ott, Adrian Wiestner, Wyndham H Wilson, Elías Campo, Luis Hernandez
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  ABSTRACT: PURPOSE: MicroRNAs (miRs) are post-transcriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRs and their relationship with clinicopathological and biological relevant features in leukemic mantle cell lymphomas (MCL). EXPERIMENTAL DESIGN: Expression profiling of 664 miRs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCL. Statistical and bioinformatic analysis were performed to define miRs associated with different clinicopathological parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRs. The prognostic value of miR-34a was investigated in two independent series of 29 leukemic and 50 nodal MCL. RESULTS: Robust consensus clustering defined two main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity and nodal clinical presentation. Supervised analyses regarding IGHV and SOX11 categories identified 17 and 22 miRs differentially expressed, respectively. Enriched targets of these miRs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling and chromatin modification. Additionally, we found seven miRs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in two independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene. CONCLUSIONS: We have identified miRs and target pathways related to clinical and biological variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL.
  Clinical Cancer Research 05/2013; · 7.74 Impact Factor
• Article: SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma.

  Maria Carmela Vegliante, Jara Palomero, Patricia Pérez-Galán, Gaël Roué, Giancarlo Castellano, Alba Navarro, Guillem Clot, Alexandra Moros, Helena Suárez-Cisneros, Sílvia Beà, Luis Hernández, Anna Enjuanes, Pedro Jares, Neus Villamor, Dolors Colomer, José Ignacio Martín-Subero, Elias Campo, Virginia Amador
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  ABSTRACT: Mantle cell lymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that it may be an important element in the development of this tumor but its potential function is not known. Here, we show that SOX11 promotes tumor growth in a MCL-xenotransplant mouse model. Using ChIP-chip analysis combined with gene expression profiling upon SOX11 knockdown, we identify target genes and transcriptional programs regulated by SOX11 including the block of mature B-cell differentiation, modulation of cell cycle, apoptosis and stem cell development. PAX5 emerges as one of the major SOX11 direct targets. SOX11 silencing downregulates PAX5, induces BLIMP1 expression and promotes the shift from a mature B-cell into the initial plasmacytic differentiation phenotype, in both primary tumor cells and in an in vitro model. Our results suggest that SOX11 contributes to tumor development by altering the terminal B-cell differentiation program of MCL and provide perspectives that may have clinical implications in the diagnosis and design of new therapeutic strategies.
  Blood 01/2013; · 9.90 Impact Factor
• Article: CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma.

  Itziar Salaverria, Cristina Royo, Alejandra Carvajal-Cuenca, Guillem Clot, Alba Navarro, Alejandra Valera, Joo Y Song, Renata Woroniecka, Grzegorz Rymkiewicz, Wolfram Klapper, [......], Philippe Gaulard, German Ott, Andreas Rosenwald, Armando Lopez-Guillermo, Leticia Quintanilla-Martinez, Nancy L Harris, Elaine S Jaffe, Reiner Siebert, Elias Campo, Sílvia Beà
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  ABSTRACT: Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14)(q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11-positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients.
  Blood 12/2012; · 9.90 Impact Factor
• Source

  Available from: Ivo Gut

  Article: Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia.

  Marta Kulis, Simon Heath, Marina Bibikova, Ana C Queirós, Alba Navarro, Guillem Clot, Alejandra Martínez-Trillos, Giancarlo Castellano, Isabelle Brun-Heath, Magda Pinyol, [......], Jian-Bing Fan, Víctor Quesada, Xose S Puente, David G Pisano, Alfonso Valencia, Armando López-Guillermo, Ivo Gut, Carlos López-Otín, Elías Campo, José I Martín-Subero
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  ABSTRACT: We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.
  Nature Genetics 10/2012; · 35.53 Impact Factor
• Article: Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features.

  Alba Navarro, Guillem Clot, Cristina Royo, Pedro Jares, Anastasia Hadzidimitriou, Andreas Agathangelidis, Vasilis Bikos, Nikos Darzentas, Theodora Papadaki, Itziar Salaverria, [......], Birgitta Sander, German Ott, Andreas Rosenwald, Dolors Colomer, Eva Giné, Reiner Siebert, Armando Lopez-Guillermo, Kostas Stamatopoulos, Sílvia Beà, Elías Campo
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  ABSTRACT: Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior. Cancer Res; 72(20); 5307-16. ©2012 AACR.
  Cancer Research 08/2012; 72(20):5307-5316. · 7.86 Impact Factor
• Article: NOTCH1 mutations in chronic lymphocytic leukemia with trisomy 12.

  Cristina López, Julio Delgado, Dolors Costa, Laura Conde, Gabriela Ghita, Neus Villamor, Alba Navarro, Maite Cazorla, Cándida Gómez, Amparo Arias, Concha Muñoz, Tycho Baumann, María Rozman, Marta Aymerich, Dolors Colomer, Francesc Cobo, Elías Campo, Armando López-Guillermo, Emili Montserrat, Ana Carrió
  Genes Chromosomes and Cancer 07/2012; 51(11):1064-5. · 3.31 Impact Factor
• Article: Different distribution of NOTCH1 mutations in chronic lymphocytic leukemia with isolated trisomy 12 or associated with other chromosomal alterations.

  Cristina López, Julio Delgado, Dolors Costa, Laura Conde, Gabriela Ghita, Neus Villamor, Alba Navarro, Maite Cazorla, Cándida Gómez, Amparo Arias, Concha Muñoz, Tycho Baumann, María Rozman, Marta Aymerich, Dolors Colomer, Francesc Cobo, Elías Campo, Armando López-Guillermo, Emili Montserrat, Ana Carrió
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  ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries. Chromosomal abnormalities commonly found using conventional cytogenetics and FISH are del(11)(q22-23), trisomy 12, del(13)(q14), and del(17)(p13). Trisomy 12 is the most frequent numerical abnormality in CLL. It can appear isolated or associated with other chromosomal aberrations, including t(14;18)(q32;q21) and trisomy 18. The aim of this study was to determine whether CLL patients with isolated trisomy 12 or associated with other chromosomal alterations have different clinico-pathological features, including a different distribution NOTCH1 mutation. Patients were classified into four groups: Group 1, isolated trisomy 12 (n=14); Group 2, trisomy 12 plus trisomy 18 (n=4); Group 3, trisomy 12 plus t(14;18) (n=8); and Group 4: patients with trisomy 12 plus other abnormalities not involving BCL2 (n=28). The Binet stage and expression of ZAP70 were significantly different among cytogenetic groups. NOTCH1 mutations were detected in 6/12 (50%) patients from Group 1, 4/25 (16%) patients from Group 4, and in no patient from groups 2 and 3 (P=0.020). Patients in Group 2 had a more rapid disease progression (median Treatment-free Survival 2 months) as against patients from Groups 1 (50 months), 3 (69 months), or 4 (68 months; P=0.001). These findings indicate that the distribution of NOTCH1 mutations in CLL with trisomy 12 is heterogeneous and that the presence of additional chromosomal abnormalities such as trisomy 18 could change the prognosis of these patients.
  Genes Chromosomes and Cancer 05/2012; 51(9):881-9. · 3.31 Impact Factor
• Article: Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression.

  Elena M Hartmann, Sílvia Beà, Alba Navarro, Vanessa Trapp, Elías Campo, German Ott, Andreas Rosenwald
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  ABSTRACT: Mantle cell lymphoma is an aggressive, non-curable B-cell lymphoma, characterized by the translocation t(11;14)(q13;q32) involving CCND1 and a high number of additional genetic alterations. Chromosomal gains of 7p are frequent in mantle cell lymphoma, with insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3 aka IMP3) being the most upregulated gene in this region. IGF2BP3 is a member of the IGF II mRNA-BP family, and increased IGF2BP3 expression is associated with an aggressive behavior in many malignant tumors. We here analyze selected genes related to IGF signaling in gene expression and genomic array data of 8 mantle cell lymphoma cell lines and 12 primary mantle cell lymphomas and study IGF2BP3 protein expression in 172 well-characterized primary mantle cell lymphomas by immunohistochemistry. The majority of mantle cell lymphoma cell lines and primary cases showed elevated IGF2BP3 mRNA expression and a subset also expressed the IGF1 and IGF2 receptors. On the protein level, 66 of 172 primary mantle cell lymphomas showed IGF2BP3 expression in >50% of tumor cells, and strong IGF2BP3 protein expression was highly associated with increased proliferation as measured by the Ki-67 index, but not with overall survival of mantle cell lymphoma patients. Only a subset of mantle cell lymphomas with marked IGF2BP3 expression had an underlying chromosomal gain in 7p, suggesting that additional mechanisms are involved in the upregulation of IGF2BP3 in mantle cell lymphoma. In seven paired mantle cell lymphoma samples, IGF2BP3 protein expression remained constant between primary diagnosis and relapse. Increased IGF2BP3 expression and, potentially, enhanced IGF signaling may contribute proproliferative stimuli in the evolution of mantle cell lymphoma tumor cells.
  Modern Pathology 05/2012; 25(9):1227-35. · 4.79 Impact Factor
• Article: Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.

  Víctor Quesada, Laura Conde, Neus Villamor, Gonzalo R Ordóñez, Pedro Jares, Laia Bassaganyas, Andrew J Ramsay, Sílvia Beà, Magda Pinyol, Alejandra Martínez-Trillos, [......], Heinz Himmelbauer, Mónica Bayés, Simon Heath, Marta Gut, Ivo Gut, Xavier Estivill, Armando López-Guillermo, Xose S Puente, Elías Campo, Carlos López-Otín
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  ABSTRACT: Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.
  Nature Genetics 12/2011; 44(1):47-52. · 35.53 Impact Factor
• Article: A new genetic abnormality leading to TP53 gene deletion in chronic lymphocytic leukaemia.

  Cristina López, Tycho Baumann, Dolors Costa, Mónica López-Guerra, Alba Navarro, Cándida Gómez, Amparo Arias, Concha Muñoz, María Rozman, Neus Villamor, Dolors Colomer, Emili Montserrat, Elías Campo, Ana Carrió
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  ABSTRACT: The analysis of chromosomal abnormalities provides significant prognostic information in patients with chronic lymphocytic leukaemia (CLL), a disease with a highly heterogeneous clinical course. Chromosomal abnormalities commonly found are trisomy 12, del(13)(q14), del(11)(q22-23), del(17)(p13) and del(6)(q21). Translocations are present in some patients and affect regions recurrently involved in CLL. This report describes the clinical and pathological characteristics of four CLL patients showing a new recurrent chromosomal abnormality dic(8;17)(p11;p11), that implied loss of the TP53 gene in all cases. In addition, TP53 gene was mutated in three out of four patients. Mechanically, Low Copy Repeats (LCR) in 17p12 and 8p11 may explain the origin of the translocation by non-allelic homologous recombination (NAHR). Isolated dic(8;17)(p11;p11) in patients with mutated IGHV genes status may not have the same prognostic impact as other mutations or deletions affecting the TP53 gene. Larger series are needed to better evaluate the clinical impact of this chromosomal aberration during the course of the disease.
  British Journal of Haematology 12/2011; 156(5):612-8. · 4.94 Impact Factor
• Article: Molecular pathogenesis of mantle cell lymphoma: new perspectives and challenges with clinical implications.

  Alba Navarro, Cristina Royo, Luis Hernández, Pedro Jares, Elías Campo
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  ABSTRACT: Mantle cell lymphoma (MCL) is a B-cell neoplasia genetically characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of its target gene CCND1. The aggressive clinical behavior of this tumor has been considered to be influenced by its genetic and molecular pathogenesis that integrates an accumulation of many chromosomal aberrations associated with frequent alterations in cell cycle and DNA damage response mechanisms and activation of cell survival pathways. Recent studies aimed to define new chromosomal regions, target genes, and signaling pathways that may contribute to the pathogenesis of this tumor. A subset of patients presenting with a leukemic and non-nodal disease and following a more indolent clinical evolution seem to have some differences in their chromosomal and genomic profiles compared to patients with conventional MCL. The new studies are opening new perspectives on the pathogenesis of this lymphoma that may influence our clinical practice in the diagnosis and management of patients.
  Seminars in Hematology 07/2011; 48(3):155-65. · 3.99 Impact Factor
• Source

  Available from: Manel Juan Otero

  Article: Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.

  Xose S Puente, Magda Pinyol, Víctor Quesada, Laura Conde, Gonzalo R Ordóñez, Neus Villamor, Georgia Escaramis, Pedro Jares, Sílvia Beà, Marcos González-Díaz, [......], Lucy A Stebbings, P Andrew Futreal, Michael R Stratton, Peter J Campbell, Ivo Gut, Armando López-Guillermo, Xavier Estivill, Emili Montserrat, Carlos López-Otín, Elías Campo
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  ABSTRACT: Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
  Nature 06/2011; 475(7354):101-5. · 36.28 Impact Factor
• Source

  Available from: Silvia Bea

  Article: Identification of methylated genes associated with aggressive clinicopathological features in mantle cell lymphoma.

  Anna Enjuanes, Verònica Fernàndez, Luis Hernández, Alba Navarro, Sílvia Beà, Magda Pinyol, Armando López-Guillermo, Andreas Rosenwald, German Ott, Elías Campo, Pedro Jares
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  ABSTRACT: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours.
  PLoS ONE 01/2011; 6(5):e19736. · 4.09 Impact Factor
• Article: Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma.

  Verònica Fernàndez, Olga Salamero, Blanca Espinet, Francesc Solé, Cristina Royo, Alba Navarro, Francisca Camacho, Sílvia Beà, Elena Hartmann, Virginia Amador, [......], Stefano A Pileri, Francesc Bosch, Miguel A Piris, Emili Montserrat, German Ott, Andreas Rosenwald, Armando López-Guillermo, Pedro Jares, Sergi Serrano, Elías Campo
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  ABSTRACT: Mantle cell lymphoma (MCL) is typically a very aggressive disease with poor outcomes, but some cases display an indolent behavior that might not necessitate treatment at diagnosis. To define molecular criteria that might permit recognition of such cases, we compared the clinicopathologic features, gene expression, and genomic profile of patients who had indolent or conventional disease (iMCL or cMCL). Patients with iMCL displayed nonnodal leukemic disease with predominantly hypermutated IGVH and noncomplex karyotypes. iMCL and cMCL shared a common gene expression profile that differed from other leukemic lymphoid neoplasms. However, we identified a signature of 13 genes that was highly expressed in cMCL but underexpressed in iMCL. SOX11 was notable in this signature and we confirmed a restriction of SOX11 protein expression to cMCL. To validate the potential use of SOX11 as a biomarker for cMCL, we evaluated SOX11 protein expression in an independent series of 112 cases of MCL. Fifteen patients with SOX11-negative tumors exhibited more frequent nonnodal presentation and better survival compared with 97 patients with SOX11-positive MCL (5-year overall survival of 78% versus 36%, respectively; P = 0.001). In conclusion, we defined nonnodal presentation, predominantly hypermutated IGVH, lack of genomic complexity, and absence of SOX11 expression as qualities of a specific subtype of iMCL with excellent outcomes that might be managed more conservatively than cMCL.
  Cancer Research 02/2010; 70(4):1408-18. · 7.86 Impact Factor
• Source

  Available from: Silvia Bea

  Article: MicroRNA expression, chromosomal alterations, and immunoglobulin variable heavy chain hypermutations in Mantle cell lymphomas.

  Alba Navarro, Sílvia Beà, Verónica Fernández, Miriam Prieto, Itziar Salaverria, Pedro Jares, Elena Hartmann, Anna Mozos, Armando López-Guillermo, Neus Villamor, Dolors Colomer, Xavier Puig, German Ott, Francesc Solé, Sergi Serrano, Andreas Rosenwald, Elías Campo, Luis Hernández
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  ABSTRACT: The contribution of microRNAs (miR) to the pathogenesis of mantle cell lymphoma (MCL) is not well known. We investigated the expression of 86 mature miRs mapped to frequently altered genomic regions in MCL in CD5(+)/CD5(-) normal B cells, reactive lymph nodes, and purified tumor cells of 17 leukemic MCL, 12 nodal MCL, and 8 MCL cell lines. Genomic alterations of the tumors were studied by single nucleotide polymorphism arrays and comparative genomic hybridization. Leukemic and nodal tumors showed a high number of differentially expressed miRs compared with purified normal B cells, but only some of them were commonly deregulated in both tumor types. An unsupervised analysis of miR expression profile in purified leukemic MCL cells revealed two clusters of tumors characterized by different mutational status of the immunoglobulin genes, proliferation signature, and number of genomic alterations. The expression of most miRs was not related to copy number changes in their respective chromosomal loci. Only the levels of miRs included in the miR-17-92 cluster were significantly related to genetic alterations at 13q31. Moreover, overexpression of miR-17-5p/miR-20a from this cluster was associated with high MYC mRNA levels in tumors with a more aggressive behavior. In conclusion, the miR expression pattern of MCL is deregulated in comparison with normal lymphoid cells and distinguishes two subgroups of tumors with different biological features.
  Cancer Research 09/2009; 69(17):7071-8. · 7.86 Impact Factor
• Article: EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.

  Maria Paola Martelli, Gabriella Sozzi, Luis Hernandez, Valentina Pettirossi, Alba Navarro, Davide Conte, Patrizia Gasparini, Federica Perrone, Piergiorgio Modena, Ugo Pastorino, [......], Angelo Sidoni, Shigeo Nakamura, Marcello Gambacorta, Pedro Luis Fernández, Jose Ramirez, John K C Chan, Walter Franco Grigioni, Elias Campo, Stefano A Pileri, Brunangelo Falini
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  ABSTRACT: A fusion gene, echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK), with transforming activity has recently been identified in a subset of non-small cell lung cancer (NSCLC), but its pathogenetic, diagnostic, and therapeutic roles remain unclear. Both frequency and type of EML4-ALK transcripts were investigated by reverse transcription PCR in 120 frozen NSCLC specimens from Italy and Spain; non-neoplastic lung tissues taken far from the tumor were used as controls. In cases carrying the fusion transcript, we determined EML4-ALK gene and protein levels using fluorescence in situ hybridization, Western blotting, and immunoprecipitation. We also analyzed ALK protein levels in paraffin samples from 662 NSCLC specimens, including the 120 cases investigated in the molecular studies. EML4-ALK transcripts (variants 1 and 3) were detected in 9 of 120 NSCLC samples but were not specific for NSCLC since they were also found in non-cancerous lung tissues taken far from the tumor. Notably, no transcripts were detected in matching tumor samples from these patients. Fluorescence in situ hybridization analysis of cases expressing EML4-ALK transcripts showed that only a minority of cells harbored the EML4-ALK gene. None of these cases was found to express the EML4-ALK protein as examined by immunohistochemistry, Western blotting, and immunoprecipitation. The EML4-ALK transcript cannot be regarded as a specific diagnostic tool for NSCLC. Our results show therefore that the causal role and value of EML4-ALK as a therapeutic target remain to be defined.
  American Journal Of Pathology 02/2009; 174(2):661-70. · 4.89 Impact Factor
• Article: Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling.

  Sílvia Beà, Itziar Salaverria, Lluís Armengol, Magda Pinyol, Verónica Fernández, Elena M Hartmann, Pedro Jares, Virginia Amador, Luís Hernández, Alba Navarro, German Ott, Andreas Rosenwald, Xavier Estivill, Elias Campo
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  ABSTRACT: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. However, only a limited number of target genes have been identified. We have studied 10 MCL cell lines and 28 primary tumors with a combination of a high-density single-nucleotide polymorphism array and gene expression profiling. We detected highly altered genomes in the majority of the samples with a high number of partial uniparental disomies (UPDs). The UPD at 17p was one of the most common, and it was associated with TP53 gene inactivation. Homozygous deletions targeted 4 known tumor suppressor genes (CDKN2C, BCL2L11, CDKN2A, and RB1) and 6 new genes (FAF1, MAP2, SP100, MOBKL2B, ZNF280A, and PRAME). Gene amplification coupled with overexpression was identified in 35 different regions. The most recurrent amplified regions were 11q13.3-q13.5, 13q31.3, and 18q21.33, which targeted CCND1, C13orf25, and BCL2, respectively. Interestingly, the breakpoints flanking all the genomic alterations, including UPDs, were significantly associated with genomic regions enriched in copy number variants and segmental duplications, suggesting that the recombination at these regions may play a role in the genomic instability of MCL. This integrative genomic analysis has revealed target genes that may be potentially relevant in MCL pathogenesis.
  Blood 12/2008; 113(13):3059-69. · 9.90 Impact Factor