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53. Revised International Prognostic Index and genetic alterations are associated with early failure to R‐CHOP in patients with diffuse large B‐cell lymphoma.

Author

Dlouhy, Ivan, Karube, Kennosuke, Enjuanes, Anna, Salaverria, Itziar, Nadeu, Ferran, Ramis‐Zaldivar, Juan Enric, Valero, Juan G., Rivas‐Delgado, Alfredo, Magnano, Laura, Martin‐García, David, Pérez‐Galán, Patricia, Clot, Guillem, Rovira, Jordina, Jares, Pedro, Balagué, Olga, Giné, Eva, Mozas, Pablo, Briones, Javier, Sancho, Juan‐Manuel, and Salar, Antonio

Subjects
ANTINEOPLASTIC combined chemotherapy protocols, CELL cycle regulation, EXTRACELLULAR matrix, GENE expression profiling, DIFFUSE large B-cell lymphomas, TUMOR microenvironment
Abstract

Summary: Relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico‐biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next‐generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety‐seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2‐microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R‐IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R‐IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R‐IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over‐representation of gene sets related to extra‐cellular matrix and tumour microenvironment. [ABSTRACT FROM AUTHOR]

Published
2022
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54. The Association between Common Vitamin D Receptor Gene Variations and Osteoporosis: A Participant-Level Meta-Analysis

Author

Uitterlinden, André G., Ralston, Stuart H., Brandi, Maria Luisa, Carey, Alisoun H., Grinberg, Daniel, Langdahl, Bente L., Lips, Paul, Lorenc, Roman, Obermayer-Pietsch, Barbara, Reeve, Jonathan, Reid, David M., Amidei, Antonietta, Bassiti, Amelia, Bustamante, Mariona, Husted, Lise Bjerre, Diez-Perez, Adolfo, Dobnig, Harald, Dunning, Alison M., Enjuanes, Anna, Fahrleitner-Pammer, Astrid, Fang, Yue, Karczmarewicz, Elzbieta, Kruk, Marcin, van Leeuwen, Johannes P.T.M., Mavilia, Carmelo, van Meurs, Joyce B.J., Mangion, Jon, McGuigan, Fiona E.A., Pols, Huibert A.P., Renner, Wilfried, Rivadeneira, Fernando, van Schoor, Natasja M., Scollen, Serena, Sherlock, Rachael E., and Ioannidis, John P.A.

Published
2006

55. IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

Author

Barcelona Supercomputing Center, Nadeu, Ferran, Mas-de-les-Valls, Rut, Navarro, Alba, Royo, Romina, Martín, Silvia, Villamor, Neus, Suárez-Cisneros, Helena, Mares, Rosó, Lu, Junyan, Enjuanes, Anna, Rivas-Delgado, Alfredo, Aymerich, Marta, Baumann, Tycho, Colomer, Dolors, Delgado, Julio, Morin, Ryan D., Zenz, Thorsten, Puente, Xose S., Campbell, Peter J., Beà, Sílvia, Maura, Francesco, Campo, Elías, Barcelona Supercomputing Center, Nadeu, Ferran, Mas-de-les-Valls, Rut, Navarro, Alba, Royo, Romina, Martín, Silvia, Villamor, Neus, Suárez-Cisneros, Helena, Mares, Rosó, Lu, Junyan, Enjuanes, Anna, Rivas-Delgado, Alfredo, Aymerich, Marta, Baumann, Tycho, Colomer, Dolors, Delgado, Julio, Morin, Ryan D., Zenz, Thorsten, Puente, Xose S., Campbell, Peter J., Beà, Sílvia, Maura, Francesco, and Campo, Elías

Abstract

Immunoglobulin (Ig) gene rearrangements and oncogenic translocations are routinely assessed during the characterization of B cell neoplasms and stratification of patients with distinct clinical and biological features, with the assessment done using Sanger sequencing, targeted next-generation sequencing, or fluorescence in situ hybridization (FISH). Currently, a complete Ig characterization cannot be extracted from whole-genome sequencing (WGS) data due to the inherent complexity of the Ig loci. Here, we introduce IgCaller, an algorithm designed to fully characterize Ig gene rearrangements and oncogenic translocations from short-read WGS data. Using a cohort of 404 patients comprising different subtypes of B cell neoplasms, we demonstrate that IgCaller identifies both heavy and light chain rearrangements to provide additional information on their functionality, somatic mutational status, class switch recombination, and oncogenic Ig translocations. Our data thus support IgCaller to be a reliable alternative to Sanger sequencing and FISH for studying the genetic properties of the Ig loci., We are indebted to the Genomics Core Facility of the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for the technical support, to R. Siebert and D. Huebschmann for sharing the CSR regions, and to K. Stamatopoulos, E. Vlachonikola and F. Psomopoulos for their helpful comments on the manuscript. We thank R. Eils, P. Lichter, C. von Kalle, S. Fröhling, H. Glimm, M. Zapatka, S. Wolf, K. Beck, and J. Kirchhof for infrastructure and pipeline development within DKFZ-HIPO and NCT POP. This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund “Una manera de hacer Europa” (PMP15/00007 to E.C.), the “la Caixa” Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221 to E.C.), the National Institute of Health “Molecular Diagnosis, Prognosis, and Therapeutic Targets in Mantle Cell Lymphoma” (P01CA229100 to E.C.), and CERCA Programme/Generalitat de Catalunya. F.N. is supported by a pre-doctoral fellowship of the Ministerio de Economía y Competitividad (BES-2016-076372). F.M. is supported by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). E.C. is an Academia Researcher of the “Institució Catalana de Recerca i Estudis Avançats” (ICREA) of the Generalitat de Catalunya. This work was partially developed at the Centre Esther Koplowitz (CEK, Barcelona, Spain)., Peer Reviewed, Postprint (published version)

Published
2020

56. IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

Author

Nadeu, Ferran; https://orcid.org/0000-0003-2910-9440, Mas-de-Les-Valls, Rut, Navarro, Alba, Royo, Romina, Martín, Silvia, Villamor, Neus; https://orcid.org/0000-0001-6538-4111, Suárez-Cisneros, Helena, Mares, Rosó, Lu, Junyan, Enjuanes, Anna, Rivas-Delgado, Alfredo; https://orcid.org/0000-0003-0385-3415, Aymerich, Marta, Baumann, Tycho, Colomer, Dolors, Delgado, Julio, Morin, Ryan D; https://orcid.org/0000-0003-2932-7800, Zenz, Thorsten; https://orcid.org/0000-0001-7890-9845, Puente, Xose S; https://orcid.org/0000-0001-9525-1483, Campbell, Peter J; https://orcid.org/0000-0002-3921-0510, Beà, Sílvia; https://orcid.org/0000-0001-7192-2385, Maura, Francesco; https://orcid.org/0000-0002-5017-1620, Campo, Elías; https://orcid.org/0000-0001-9850-9793, Nadeu, Ferran; https://orcid.org/0000-0003-2910-9440, Mas-de-Les-Valls, Rut, Navarro, Alba, Royo, Romina, Martín, Silvia, Villamor, Neus; https://orcid.org/0000-0001-6538-4111, Suárez-Cisneros, Helena, Mares, Rosó, Lu, Junyan, Enjuanes, Anna, Rivas-Delgado, Alfredo; https://orcid.org/0000-0003-0385-3415, Aymerich, Marta, Baumann, Tycho, Colomer, Dolors, Delgado, Julio, Morin, Ryan D; https://orcid.org/0000-0003-2932-7800, Zenz, Thorsten; https://orcid.org/0000-0001-7890-9845, Puente, Xose S; https://orcid.org/0000-0001-9525-1483, Campbell, Peter J; https://orcid.org/0000-0002-3921-0510, Beà, Sílvia; https://orcid.org/0000-0001-7192-2385, Maura, Francesco; https://orcid.org/0000-0002-5017-1620, and Campo, Elías; https://orcid.org/0000-0001-9850-9793

Abstract

Immunoglobulin (Ig) gene rearrangements and oncogenic translocations are routinely assessed during the characterization of B cell neoplasms and stratification of patients with distinct clinical and biological features, with the assessment done using Sanger sequencing, targeted next-generation sequencing, or fluorescence in situ hybridization (FISH). Currently, a complete Ig characterization cannot be extracted from whole-genome sequencing (WGS) data due to the inherent complexity of the Ig loci. Here, we introduce IgCaller, an algorithm designed to fully characterize Ig gene rearrangements and oncogenic translocations from short-read WGS data. Using a cohort of 404 patients comprising different subtypes of B cell neoplasms, we demonstrate that IgCaller identifies both heavy and light chain rearrangements to provide additional information on their functionality, somatic mutational status, class switch recombination, and oncogenic Ig translocations. Our data thus support IgCaller to be a reliable alternative to Sanger sequencing and FISH for studying the genetic properties of the Ig loci.

Published
2020

57. The U1 Spliceosomal RNA: A Novel Non-Coding Hotspot Driver Mutation Independently Associated with Clinical Outcome in Chronic Lymphocytic Leukemia

Author

Nadeu, Ferran, primary, Shuai, Shimin, primary, Diaz-Navarro, Ander, primary, López, Irene, primary, Martín, Silvia, primary, Suzuki, Hiromichi, primary, Royo, Romina, primary, Clot, Guillem, primary, Delgado, Julio, primary, Baumann, Tycho, primary, Lu, Junyan, primary, Navarro, Alba, primary, Kulis, Marta, primary, Kumar, Sachin A, primary, Gutierrez-Fernandez, Ana, primary, Alcoceba, Miguel, primary, González, Marcos, primary, Colado, Enrique, primary, Ramirez Payer, Angel, primary, Capdevila, Cristina, primary, Osuna, Miguel, primary, Aymerich, Marta, primary, Mares, Rosó, primary, Lopez-Guerra, Monica, primary, Magnano, Laura, primary, Mozas, Pablo, primary, Rivas-Delgado, Alfredo, primary, Terol, Maria Jose, primary, Enjuanes, Anna, primary, Huber, Wolfgang, primary, Lopez-Guillermo, Armando, primary, Beà, Sílvia, primary, Martin-Subero, José I., primary, Zenz, Thorsten, primary, Taylor, Michael D, primary, Colomer, Dolors, primary, Puente, Xose S, primary, Stein, Lincoln D, primary, and Campo, Elias, primary

Published
2019
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58. Mutational Landscape, Copy Number Alterations and Tumor Burden Assessed By Cell-Free DNA in Diffuse Large B-Cell Lymphoma

Author

Rivas-Delgado, Alfredo, primary, Nadeu, Ferran, additional, Enjuanes, Anna, additional, Casanueva, Sebastián, additional, Magnano, Laura, additional, Castrejón de Anta, Natalia, additional, Rovira, Jordina, additional, Dlouhy, Ivan, additional, Mozas, Pablo, additional, Martín, Silvia, additional, Osuna, Miguel, additional, Baumann, Tycho, additional, Delgado, Julio, additional, Olga, Balagué, additional, Beà, Sílvia, additional, Villamor, Neus, additional, Setoain, Xavier, additional, Campo, Elías, additional, Gine, Eva, additional, and Lopez-Guillermo, Armando, additional

Published
2019
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59. Large B-Cell Lymphomas in Pediatric and Young Adults Display Clinically Relevant Molecular Features Distinguishable from Adult Counterparts

Author

Ramis-Zaldivar, Joan Enric, primary, Gonzalez-Farre, Blanca, additional, Olga, Balagué, additional, Celis, Verónica, additional, Nadeu, Ferran, additional, Andrés, Mara, additional, Martin-Guerrero, Idoia, additional, Garrido, Marta, additional, Gaafar, Ayman, additional, Suñol, Mariona, additional, Bárcena, Carmen, additional, Garcia-Bragado, Federico, additional, Andión, Maitane, additional, Azorín, Daniel, additional, Astigarraga, Itziar, additional, Sagaseta, Maria, additional, Sábado, Constantino, additional, Gallego, Soledad, additional, Verdú, Jaime, additional, Delgado, Raphael F, additional, Tapia, Gustavo, additional, Rivas-Delgado, Alfredo, additional, Dlouhy, Ivan, additional, Salmerón-Villalobos, Julia, additional, Clot, Guillem, additional, Enjuanes, Anna, additional, Lopez-Guillermo, Armando, additional, Galera, Pallavi, additional, Oberley, Matthew J., additional, Quintanilla-Martinez, Leticia, additional, Jaffe, Elaine S., additional, Campo, Elias, additional, and Salaverria, Itziar, additional

Published
2018
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60. Clinical Impact of the Quantitative Subclonal Architecture in Chronic Lymphocytic Leukemia

Author

Nadeu, Ferran, primary, Delgado, Julio, additional, Clot, Guillem, additional, Martín-García, David, additional, Baumann, Tycho, additional, Pinyol, Magda, additional, Jares, Pedro, additional, Beà, Sílvia, additional, Salaverria, Itziar, additional, Navarro, Alba, additional, Suárez-Cisneros, Helena, additional, Aymerich, Marta, additional, Rozman, Maria, additional, Villamor, Neus, additional, Colomer, Dolors, additional, González, Marcos, additional, Alcoceba, Miguel, additional, Terol, María José, additional, Colado, Enrique, additional, López-Guillermo, Armando, additional, Puente, Xose S, additional, Lopez-Otin, Carlos, additional, Enjuanes, Anna, additional, and Campo, Elias, additional

Published
2016
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61. Aberrant Expression of the SOX11 Oncogene in Mantle Cell Lymphoma Is Associated with Activation and De Novo 3D Looping of a Distant Enhancer Element

Author

Vilarrasa-Blasi, Roser, primary, Queirós, Ana C., additional, Beekman, Renée, additional, Russiñol, Nuria, additional, Castellano, Giancarlo, additional, Blanc, Julie, additional, Serra, François, additional, Beà, Sílvia, additional, Kulis, Marta, additional, Verdaguer-Dot, Núria, additional, Enjuanes, Anna, additional, Bergmann, Anke, additional, Salaverria, Itziar, additional, van de Werken, Harmen J.G., additional, Datta, Avik, additional, Flicek, Paul, additional, Martens, Joost H.A., additional, Stunnenberg, Hendrik G., additional, Gut, Marta, additional, Marti-Renom, Marc A., additional, Gut, Ivo G., additional, Siebert, Reiner, additional, Campo, Elias, additional, and Martin-Subero, José I., additional

Published
2016
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62. Integrating Genomic Alterations in Diffuse Large B-Cell Lymphoma Identifies New Relevant Pathways and Potential Therapeutic Targets

Author

Dlouhy, Ivan, primary, Karube, Kennosuke, additional, Enjuanes, Anna, additional, Martín-García, David, additional, Nadeu, Ferran, additional, Ordoñez, Gonzalo R, additional, Rovira, Jordina, additional, Royo, Cristina, additional, Navarro, Alba, additional, Gonzalez, Blanca, additional, Castellano, Giancarlo, additional, Rubio-Perez, Carlota, additional, Tamborero, David, additional, Briones, Javier, additional, Salar, Antonio, additional, Sancho, Juan-Manuel, additional, Mercadal, Santiago, additional, Gonzalez Barca, Eva, additional, Escoda, Lourdes, additional, Hiroaki, Miyoshi, additional, Ohshima, Koichi, additional, Kato, Koji, additional, Akashi, Koichi, additional, Mozos, Anna, additional, Colomo, Lluis, additional, Alcoceba, Miguel, additional, Valera, Alexandra, additional, Carrio, Anna, additional, Lopez-Bigas, Nuria, additional, Schmitz, Roland, additional, Staudt, Louis, additional, Jares, Pedro, additional, Salaverria, Itziar, additional, López-Guillermo, Armando, additional, and Campo, Elias, additional

Published
2016
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63. MYD88 L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome

Author

Rovira, Jordina, primary, Karube, Kennosuke, additional, Valera, Alexandra, additional, Colomer, Dolors, additional, Enjuanes, Anna, additional, Colomo, Lluís, additional, Martínez-Trillos, Alejandra, additional, Giné, Eva, additional, Dlouhy, Ivan, additional, Magnano, Laura, additional, Delgado, Julio, additional, Martínez, Antonio, additional, Villamor, Neus, additional, Campo, Elías, additional, and López-Guillermo, Armando, additional

Published
2016
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64. NOTCH1, TP53, and MAP2K1 Mutations in Splenic Diffuse Red Pulp Small B-cell Lymphoma Are Associated With Progressive Disease

Author

Martinez, Daniel, primary, Navarro, Alba, additional, Martinez-Trillos, Alejandra, additional, Molina-Urra, Ricardo, additional, Gonzalez-Farre, Blanca, additional, Salaverria, Itziar, additional, Nadeu, Ferran, additional, Enjuanes, Anna, additional, Clot, Guillem, additional, Costa, Dolors, additional, Carrio, Ana, additional, Villamor, Neus, additional, Colomer, Dolors, additional, Martinez, Antonio, additional, Bens, Susanne, additional, Siebert, Reiner, additional, Wotherspoon, Andrew, additional, Beà, Sílvia, additional, Matutes, Estella, additional, and Campo, Elias, additional

Published
2016
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65. Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis

Author

Corbera-Bellalta, Marc, primary, Planas-Rigol, Ester, additional, Lozano, Ester, additional, Terrades-García, Nekane, additional, Alba, Marco A, additional, Prieto-González, Sergio, additional, García-Martínez, Ana, additional, Albero, Robert, additional, Enjuanes, Anna, additional, Espígol-Frigolé, Georgina, additional, Hernández-Rodríguez, José, additional, Roux-Lombard, Pascale, additional, Ferlin, Walter G, additional, Dayer, Jean-Michel, additional, Kosco-Vilbois, Marie H, additional, and Cid, Maria C, additional

Published
2015
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66. Clinical Impact of Clonal and Subclonal TP53, SF3B1, BIRC3, and ATM Mutations in Chronic Lymphocytic Leukemia

Author

Nadeu, Ferran, primary, Delgado, Julio, additional, Royo, Cristina, additional, Bauman, Tycho, additional, Stankovic, Tatjana, additional, Pinyol, Magda, additional, Jares, Pedro, additional, Navarro, Alba, additional, Martín-García, David, additional, Beà, Sílvia, additional, Salaverria, Itziar, additional, Oldreive, Ceri, additional, Aymerich, Marta, additional, Suárez-Cisneros, Helena, additional, Rozman, Maria, additional, Villamor, Neus, additional, Colomer, Dolors, additional, López-Guillermo, Armando, additional, González, Marcos, additional, Alcoceba, Miguel, additional, Terol, María José, additional, Colado, Enrique, additional, Puente, Xose S, additional, López-Otín, Carlos, additional, Enjuanes, Anna, additional, and Campo, Elías, additional

Published
2015
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67. The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis

Author

Uitterlinden, Andre G. Ralston, Stuart H. Brandi, Maria Luisa and Carey, Alisoun H. Grinberg, Daniel Langdahl, Bente L. and Lips, Paul Lorenc, Roman Obermayer-Pietsch, Barbara Reeve, Jonathan Reid, David M. Amidei, Antonietta Bassiti, Amelia and Bustamante, Mariona Husted, Use Bjerre Diez-Perez, Adolfo and Dobnig, Harald Dunning, Alison M. Enjuanes, Anna and Fahrleitner-Pammer, Astrid Fang, Yue Karczmarewicz, Elzbieta and Kruk, Marcin van Leeuwen, Johannes P. T. M. Mavilia, Carmelo and van Meurs, Joyce B. J. Mangion, Jon McGuigan, Fiona E. A. and Pols, Huibert A. P. Renner, Wilfried Rivadeneira, Fernando and van Schoor, Natasja M. Scollen, Serena Sherlock, Rachael E. and Ioannidis, John P. A. APOSS Investigators EPOS Investigators and EPOLOS Investigators FAMOS Investigators LASA Investigators and Rotterdam Study Investigators GENOMOS Study

Subjects
musculoskeletal diseases
Abstract

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures. Design: Prospective multicenter large-scale association study. Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. Participants: 26242 participants (18405 women). Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm(2) for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

Published
2006

68. Risk of Central Nervous System (CNS) Involvement in Patients with Mantle Cell Lymphoma (MCL): Analysis of Clinico-Biological Factors in a Series of 283 Cases

Author

Giné, Eva, primary, Beà, Sílvia, additional, Navarro, Alba, additional, Martínez-Cibrián, Nuria, additional, Salaverría, Itziar, additional, Martín-García, David, additional, Jares, Pedro, additional, Pinyol, Magda, additional, Royo, Cristina, additional, Clot, Guillem, additional, Aymerich, Marta, additional, Villamor, Neus, additional, Colomo, Lluis, additional, Martínez, Antonio, additional, Valera, Alexandra, additional, Rozman, María, additional, Enjuanes, Anna, additional, Forcada, Pilar, additional, Muntanola, Anna, additional, Hartmann, Elena, additional, Rosenwald, Andreas, additional, Ott, German, additional, González, Marcos, additional, Hernández-Rivas, Jesús M, additional, Klapper, Wolfram, additional, Siebert, Reiner, additional, Wiestner, Adrian, additional, Wilson, Wyndham H., additional, Calasanz, Maria José, additional, Magnano, Laura, additional, Rovira, Jordina, additional, Colomer, Dolors, additional, Campo, Elias, additional, and Lopez-Guillermo, Armando, additional

Published
2014
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69. Results of the “Evaluation of NGS in AML-Diagnostics (ELAN)” Study – an Inter-Laboratory Comparison Performed in 10 European Laboratories

Author

Thiede, Christian, primary, Bullinger, Lars, additional, Hernández-Rivas, Jesús M, additional, Heuser, Michael, additional, Preudhomme, Claude, additional, Best, Steven, additional, Colomer, Dolors, additional, Lo Coco, Francesco, additional, Martinelli, Giovanni, additional, Schuh, Anna, additional, Benito, Rocí­o, additional, Dolnik, Anna, additional, Enjuanes, Anna, additional, Geffroy, Sandrine, additional, Lavorgna, Serena, additional, Lea, Nicholas, additional, Mason, Joanne, additional, Ottaviani, Emanuela, additional, Otto, Anne, additional, Thol, Felicitas, additional, Bhuju, Sabin, additional, Döhner, Konstanze, additional, Eberlein, Christian, additional, Hamblin, Angela, additional, Nibourel, Olivier, additional, Ottone, Tiziana, additional, Laginestra, Maria Antonella, additional, Pratcorona, Marta, additional, del Rey, Mónica, additional, and Schlesinger, Felix, additional

Published
2014
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70. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk

Author

Crowther-Swanepoel, Dalemari, Broderick, Peter, Di Bernardo, Maria Chiara, Dobbins, Sara E., Torres, Maria, Mansouri, Mahmoud, Ruiz-Ponte, Clara, Enjuanes, Anna, Rosenquist, Richard, Carracedo, Angel, Jurlander, Jesper, Campo, Elias, Juliusson, Gunnar, Montserrat, Emilio, Smedby, Karin E., Dyer, Martin J. S., Matutes, Estella, Dearden, Claire, Sunter, Nicola J., Hall, Andrew G., Mainou-Fowler, Tryfonia, Jackson, Graham H., Summerfield, Geoffrey, Harris, Robert J., Pettitt, Andrew R., Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Parker, Anton, Oscier, David, Allan, James M., Catovsky, Daniel, Houlston, Richard S., Crowther-Swanepoel, Dalemari, Broderick, Peter, Di Bernardo, Maria Chiara, Dobbins, Sara E., Torres, Maria, Mansouri, Mahmoud, Ruiz-Ponte, Clara, Enjuanes, Anna, Rosenquist, Richard, Carracedo, Angel, Jurlander, Jesper, Campo, Elias, Juliusson, Gunnar, Montserrat, Emilio, Smedby, Karin E., Dyer, Martin J. S., Matutes, Estella, Dearden, Claire, Sunter, Nicola J., Hall, Andrew G., Mainou-Fowler, Tryfonia, Jackson, Graham H., Summerfield, Geoffrey, Harris, Robert J., Pettitt, Andrew R., Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Parker, Anton, Oscier, David, Allan, James M., Catovsky, Daniel, and Houlston, Richard S.

Abstract

To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

Published
2010
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72. Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications

Author

Vegliante, Maria Carmela, primary, Royo, Cristina, additional, Palomero, Jara, additional, Salaverria, Itziar, additional, Balint, Balazs, additional, Martín-Guerrero, Idoia, additional, Agirre, Xabier, additional, Lujambio, Amaia, additional, Richter, Julia, additional, Xargay-Torrent, Silvia, additional, Bea, Silvia, additional, Hernandez, Luis, additional, Enjuanes, Anna, additional, Calasanz, María José, additional, Rosenwald, Andreas, additional, Ott, German, additional, Roman-Gomez, José, additional, Prosper, Felipe, additional, Esteller, Manel, additional, Jares, Pedro, additional, Siebert, Reiner, additional, Campo, Elias, additional, Martín-Subero, José I., additional, and Amador, Virginia, additional

Published
2011
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74. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk

Author

Crowther-Swanepoel, Dalemari, primary, Broderick, Peter, additional, Di Bernardo, Maria Chiara, additional, Dobbins, Sara E, additional, Torres, María, additional, Mansouri, Mahmoud, additional, Ruiz-Ponte, Clara, additional, Enjuanes, Anna, additional, Rosenquist, Richard, additional, Carracedo, Angel, additional, Jurlander, Jesper, additional, Campo, Elias, additional, Juliusson, Gunnar, additional, Montserrat, Emilio, additional, Smedby, Karin E, additional, Dyer, Martin J S, additional, Matutes, Estella, additional, Dearden, Claire, additional, Sunter, Nicola J, additional, Hall, Andrew G, additional, Mainou-Fowler, Tryfonia, additional, Jackson, Graham H, additional, Summerfield, Geoffrey, additional, Harris, Robert J, additional, Pettitt, Andrew R, additional, Allsup, David J, additional, Bailey, James R, additional, Pratt, Guy, additional, Pepper, Chris, additional, Fegan, Chris, additional, Parker, Anton, additional, Oscier, David, additional, Allan, James M, additional, Catovsky, Daniel, additional, and Houlston, Richard S, additional

Published
2010
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76. Genetic Variants in Apoptosis and Immunoregulation-Related Genes Are Associated with Risk of Chronic Lymphocytic Leukemia

Author

Enjuanes, Anna, primary, Benavente, Yolanda, additional, Bosch, Francesc, additional, Martín-Guerrero, Idoia, additional, Colomer, Dolors, additional, Pérez-Álvarez, Susana, additional, Reina, Oscar, additional, Ardanaz, Maria T., additional, Jares, Pedro, additional, García-Orad, Africa, additional, Pujana, Miguel A., additional, Montserrat, Emili, additional, de Sanjosé, Silvia, additional, and Campo, Elias, additional

Published
2008
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77. Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG‐63 cultures

Author

Ruiz‐Gaspa, Silvia, primary, Nogues, Xavier, additional, Enjuanes, Anna, additional, Monllau, Joan C., additional, Blanch, Josep, additional, Carreras, Ramon, additional, Mellibovsky, Leonardo, additional, Grinberg, Daniel, additional, Balcells, Susana, additional, Díez‐Perez, Adolfo, additional, and Pedro‐Botet, Juan, additional

Published
2007
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78. Functional analysis of the I.3, I.6, pII and I.4 promoters of CYP19 (aromatase) gene in human osteoblasts and their role in vitamin D and dexamethasone stimulation

Author

Enjuanes, Anna, primary, Garcia-Giralt, Natalia, additional, Supervía, August, additional, Nogués, Xavier, additional, Ruiz-Gaspà, Silvia, additional, Bustamante, Mariona, additional, Mellibovsky, Leonardo, additional, Grinberg, Daniel, additional, Balcells, Susana, additional, and Díez-Pérez, Adolfo, additional

Published
2005
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80. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATMmutations in chronic lymphocytic leukemia

Author

Nadeu, Ferran, Delgado, Julio, Royo, Cristina, Baumann, Tycho, Stankovic, Tatjana, Pinyol, Magda, Jares, Pedro, Navarro, Alba, Martín-García, David, Beà, Sílvia, Salaverria, Itziar, Oldreive, Ceri, Aymerich, Marta, Suárez-Cisneros, Helena, Rozman, Maria, Villamor, Neus, Colomer, Dolors, López-Guillermo, Armando, González, Marcos, Alcoceba, Miguel, Terol, Maria José, Colado, Enrique, Puente, Xose S., López-Otín, Carlos, Enjuanes, Anna, and Campo, Elías

Abstract

Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATMin 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATMmutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3mutations in 4.2% (2% clonal, 2.2% subclonal). ATMmutations, clonal SF3B1, and both clonal and subclonal NOTCH1mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53and clonal NOTCH1mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients.

Published
2016
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81. NOTCH1, TP53, and MAP2K1Mutations in Splenic Diffuse Red Pulp Small B-cell Lymphoma Are Associated With Progressive Disease

Author

Martinez, Daniel, Navarro, Alba, Martinez-Trillos, Alejandra, Molina-Urra, Ricardo, Gonzalez-Farre, Blanca, Salaverria, Itziar, Nadeu, Ferran, Enjuanes, Anna, Clot, Guillem, Costa, Dolors, Carrio, Ana, Villamor, Neus, Colomer, Dolors, Martinez, Antonio, Bens, Susanne, Siebert, Reiner, Wotherspoon, Andrew, Beà, Sílvia, Matutes, Estella, and Campo, Elias

Abstract

Supplemental Digital Content is available in the text.Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHVgenes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGHrearrangements in 3, with PAX5and potentially TCL1as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1and MAP2K1were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1were mutated each in single cases. No mutations were found in NOTCH2or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1(2 cases), TP53(1 case), and MAP2K1(1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior.

Published
2016
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82. IGLV3-21R110mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

Author

Syrykh, Charlotte, Pons-Brun, Berta, Russiñol, Núria, Playa-Albinyana, Heribert, Baumann, Tycho, Duran-Ferrer, Martí, Kulis, Marta, Carbó-Meix, Anna, Mozas, Pablo, Alcoceba, Miguel, González, Marcos, Navarro-Bailón, Almudena, Colado, Enrique, Payer, Ángel R., Aymerich, Marta, Terol, María J., Lu, Junyan, Knisbacher, Binyamin A., Hahn, Cynthia K., Ruiz-Gaspà, Sílvia, Enjuanes, Anna, Wu, Catherine J., Getz, Gad, Zenz, Thorsten, López-Guillermo, Armando, Martín-Subero, José I., Colomer, Dolors, Delgado, Julio, Campo, Elías, and Nadeu, Ferran

Published
2023
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83. Two New Single‐Nucleotide Polymorphisms in the COL1A1Upstream Regulatory Region and Their Relationship to Bone Mineral Density*

Author

Garcia‐Giralt, Natalia, Nogués, Xavier, Enjuanes, Anna, Puig, Jordi, Mellibovsky, Leonardo, Bay‐Jensen, Anne, Carreras, Ramon, Balcells, Susana, Díez‐Pérez, Adolfo, and Grinberg, Daniel

Abstract

Single‐nucleotide polymorphisms (SNPs) in regulatory regions of candidate genes may determine variability in bone mineral density (BMD) because they may be responsible for differences in levels of a gene product in response to external signals. Under this hypothesis, we scanned an 800‐base pair (bp) region within the COL1A1promoter, known to harbor ciselements important for in vivo expression, and we found two new polymorphisms: −1663indelT and −1997 G/T. The G to T transversion at −1997 was associated with lumbar spine BMD (p= 0.015) when tested in a cohort of 256 postmenopausal women after adjusting by age, body weight, and years since menopause; a lower degree of association was detected also for femoral neck BMD in a subgroup of 146 women in univariate analysis and after adjusting by age (p= 0.044). The polymorphism −1663indelT, which corresponds to a deletion of a T in a tract of eight T residues (−1670 to −1663), did not show significant association with BMD. Interestingly, −1663indelT is in strong linkage disequilibrium (LD) with the previously described Sp1 polymorphism of intron 1, which in this study did not show association with BMD either. Significant interaction between −1997 G/T and −1663indelT (p= 0.019), and between −1997 G/T and Sp1 (p= 0.045) was observed also. Individuals heterozygous for the three polymorphisms showed the highest mean BMD value. Gel retardation assays showed that oligonucleotides containing either the −1663 or the −1997 polymorphic sites specifically bind primary osteoblast nuclear proteins. We named these binding sites as PCOL1 and PCOL2, respectively. In summary, this study describes two new SNPs in the COL1A1promoter, which may affect bone mass determination.

Published
2002
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84. Results of the 'Evaluation of NGS in AML-Diagnostics ( ELAN)' Study - an Inter-Laboratory Comparison Performed in 10 European Laboratories

Author

Thiede, Christian, Bullinger, Lars, Hernandez-Rivas, Jesus M., Heuser, Michael, Preudhomme, Claude, Best, Steven, Colomer, Dolors, Lo Coco, Francesco, Martinelli, Giovanni, Schuh, Anna, Benito, Rocio, Dolnik, Anna, Enjuanes, Anna, Geffroy, Sandrine, Lavorgna, Serena, Lea, Nicholas, Mason, Joanne, Ottaviani, Emanuela, Otto, Anne, Thol, Felicitas, Bhuju, Sabin, Doehner, Konstanze, Eberlein, Christian, Hamblin, Angela, Olivier Nibourel, Ottone, Tiziana, Laginestra, Maria Antonella, Pratcorona, Marta, Del Rey, Monica, and Schlesinger, Felix

85. Aberrant Expression of the SOX11Oncogene in Mantle Cell Lymphoma Is Associated with Activation and De Novo3D Looping of a Distant Enhancer Element

Author

Vilarrasa-Blasi, Roser, Queirós, Ana C., Beekman, Renée, Russiñol, Nuria, Castellano, Giancarlo, Blanc, Julie, Serra, François, Beà, Sílvia, Kulis, Marta, Verdaguer-Dot, Núria, Enjuanes, Anna, Bergmann, Anke, Salaverria, Itziar, van de Werken, Harmen J.G., Datta, Avik, Flicek, Paul, Martens, Joost H.A., Stunnenberg, Hendrik G., Gut, Marta, Marti-Renom, Marc A., Gut, Ivo G., Siebert, Reiner, Campo, Elias, and Martin-Subero, José I.

Abstract

Introduction

Published
2016
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86. MYC and TP53 Alterations but Not MAPK Pathway Mutations Are Common Oncogenic Mechanisms in Follicular Dendritic Cell Sarcomas.

Author

Frigola, Gerard, Bühler, Marco, Marginet, Marta, Enjuanes, Anna, Nadeu, Ferran, Papaleo, Natalia, Salido, Marta, Haralambieva, Eugenia, Alamo, José, Garcia-Bragado, Federico, Alvarez, Ramiró, Ramos, Rafael, Aldecoa, Iban, Campo, Elías, Colomo, Lluis, and Balagué, Olga

Subjects
*DENDRITIC cells, *GRANULOMA, *GENETIC mutation, *CARCINOGENESIS, *ONCOGENES, *IMMUNOHISTOCHEMISTRY, *CELLULAR signal transduction, *GENE expression, *TUMOR suppressor genes, *MITOGEN-activated protein kinases, *SARCOMA, *EPSTEIN-Barr virus diseases
Abstract

Context.--Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation. Objective.--To identify molecular alterations driving tumorigenesis in FDCS. Design.--We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)--like FDCSs, and 8 IPTs. Results.--MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCSs or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied. Conclusions.--The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms. [ABSTRACT FROM AUTHOR]

Published
2023
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87. Clinical Impact of Clonal and Subclonal TP53, SF3B1, BIRC3, and ATMMutations in Chronic Lymphocytic Leukemia

Author

Nadeu, Ferran, Delgado, Julio, Royo, Cristina, Bauman, Tycho, Stankovic, Tatjana, Pinyol, Magda, Jares, Pedro, Navarro, Alba, Martín-García, David, Beà, Sílvia, Salaverria, Itziar, Oldreive, Ceri, Aymerich, Marta, Suárez-Cisneros, Helena, Rozman, Maria, Villamor, Neus, Colomer, Dolors, López-Guillermo, Armando, González, Marcos, Alcoceba, Miguel, Terol, María José, Colado, Enrique, Puente, Xose S, López-Otín, Carlos, Enjuanes, Anna, and Campo, Elías

Abstract

Genomic studies have provided a complete profile of somatic mutations in chronic lymphocytic leukemia (CLL). These comprehensive approaches have revealed a relatively large number of mutated genes, the adverse prognostic value of some of which has been demonstrated in a number of reports. Recent studies have shown the clinical relevance of TP53mutations at very low allele frequency. The presence and prognostic impact of minor mutated clones of other CLL driver genes and their clonal dynamics in the evolution of the disease is not well known. The goal of this study was to explore the presence of clonal and subclonal mutations of TP53, SF3B1, BIRC3,and ATMusing an ultra-deep next-generation sequencing (NGS) strategy, to define the evolution of these subclones in different time-points of the disease, and to determine their influence in the outcome of the patients.

Published
2015
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88. Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL.

Author

Rivas-Delgado A, López C, Clot G, Nadeu F, Grau M, Frigola G, Bosch-Schips J, Radke J, Ishaque N, Alcoceba M, Tapia G, Luizaga L, Barcena C, Kelleher N, Villamor N, Baumann T, Muntañola A, Sancho-Cia JM, García-Sancho AM, Gonzalez-Barca E, Matutes E, Brito JA, Karube K, Salaverria I, Enjuanes A, Wiemann S, Heppner FL, Siebert R, Climent F, Campo E, Giné E, López-Guillermo A, and Beà S

Abstract

Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations ( p  < 0.04) but more somatic variants ( p  < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 ( BCL2 ) gains and 6q and 9p21.3 ( CDKN2A/B ) deletions. PIM1 , MYD88 L265P , CD79B , TBL1XR1 , MEF2B , CIITA , EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches., Competing Interests: Ferran Nadeu has received honoraria from Janssen, AbbVie, AstraZeneca, and SOPHiA GENETICS for speaking at educational activities; has received research support from Gilead; and has licensed the use of the protected IgCaller algorithm to Diagnóstica Longwood. Tycho Baumann has received consulting fees or honoraria from Janssen, Roche, Novartis, Merck, Gilead/Kite, Incyte, Lilly, Abbvie, AstraZeneca, and BeiGene. Alejandro Martin García‐Sancho has received consulting fees or honoraria from Janssen, Roche, BMS/Celgene, Kyowa Kirin, Clinigen, EUSAPharma, Novartis, Gilead/Kite, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Ideogen, Abbvie, and BeiGene. Elías Campo has been a consultant for GenMab, and Takeda; has received research support from AstraZeneca; received honoraria from Janssen, EUSPharma, Takeda, and Roche for speaking at educational activities; and is an inventor on a Lymphoma and Leukemia Molecular Profiling Project patent “Method for subtyping lymphoma subtypes by means of expression profiling” (PCT/US2014/64161) and a bioinformatic tool (IgCaller) licensed to Diagnostic Longwood. Eva Giné has received honoraria or consulting fees from Gilead, Kite Pharma, Janssen, Genmab, Miltenyi, and Lilly; has received research support from Janssen and travel expenses from Gilead and Kite Pharma. Armando López Guillermo served on the advisory board of Roche, Celgene, Novartis, and Gilead/Kite, received grants from Celgene and Gilead/Kite, and travel expenses from Kite/Gilead. The remaining authors declare no competing interests., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Published
2024
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89. Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study.

Author

Sutton LA, Ljungström V, Enjuanes A, Cortese D, Skaftason A, Tausch E, Stano Kozubik K, Nadeu F, Armand M, Malcikova J, Pandzic T, Forster J, Davis Z, Oscier D, Rossi D, Ghia P, Strefford JC, Pospisilova S, Stilgenbauer S, Davi F, Campo E, Stamatopoulos K, Rosenquist R, and On Behalf Of The European Research Initiative On Cll Eric

Subjects
High-Throughput Nucleotide Sequencing, Humans, Mutation, Reproducibility of Results, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
Abstract

Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF <5%). We sought to investigate low-frequency mutations further by using a high-sensitivity assay containing unique molecular identifiers, which confirmed the presence of several minor subclonal mutations. Thus, while amplicon-based approaches can be adopted for somatic mutation detection with VAF >5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.

Published
2021
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90. Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments.

Author

Enjuanes A, Garcia-Giralt N, Supervia A, Nogués X, Mellibovsky L, Carbonell J, Grinberg D, Balcells S, and Díez-Pérez A

Subjects
Actins genetics, Cells, Cultured, Cytokines pharmacology, Dexamethasone pharmacology, Gonadal Steroid Hormones pharmacology, Humans, Promoter Regions, Genetic physiology, RNA, Messenger metabolism, Vitamin D pharmacology, Aromatase genetics, Gene Expression Regulation drug effects, Osteoblasts physiology
Abstract

Objective: Extragonadal estrogen biosynthesis is relevant for the regulation of bone metabolism. The aims of this paper were: (i) to examine CYP19 (aromatase) gene expression in primary cultures of osteoblasts under several hormone and cytokine treatments and (ii) to study the promoter usage of CYP19 in these cells., Methods: Primary cultures of osteoblasts were obtained from healthy donors. The effects of vitamin D and other factors on CYP19 expression were analysed by semiquantitative RT-PCR. Furthermore, CYP19 alternative promoter usage under the different treatments was characterized by RT-PCR., Results: CYP19 transcripts were detected in cultured human osteoblasts in serum-free conditions. Vitamin D, dexamethasone, 17beta-estradiol and testosterone increased transcript levels of CYP19, whereas interleukin-1beta or tumor necrosis factor alpha decreased them. Aromatase mRNA produced under treatment with vitamin D was transcribed from promoters I.4 and I.3, while stimulation with dexamethasone or dexamethasone plus vitamin D also involved promoter I.2. Testosterone activated promoters I.2 and I.4., Conclusions: Our results suggested that vitamin D, testosterone, estrogens and glucocorticoids regulate CYP19 gene expression in human primary osteoblasts and the main promoter used appears to be promoter I.4. Promoters pII and I.3 seem to be related to basal transcription and may mediate estrogen stimulation, while promoter I.2 seems to play a role in the effect of glucocorticoids. These findings indicate that vitamin D and several hormones regulate local estrogen synthesis in human osteoblasts mainly through usage of promoters I.4 and I.3.

Published
2003
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