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

Author

Kulis, Marta, primary, Heath, Simon, additional, Bibikova, Marina, additional, Queirós, Ana C, additional, Navarro, Alba, additional, Clot, Guillem, additional, Martínez-Trillos, Alejandra, additional, Castellano, Giancarlo, additional, Brun-Heath, Isabelle, additional, Pinyol, Magda, additional, Barberán-Soler, Sergio, additional, Papasaikas, Panagiotis, additional, Jares, Pedro, additional, Beà, Sílvia, additional, Rico, Daniel, additional, Ecker, Simone, additional, Rubio, Miriam, additional, Royo, Romina, additional, Ho, Vincent, additional, Klotzle, Brandy, additional, Hernández, Lluis, additional, Conde, Laura, additional, López-Guerra, Mónica, additional, Colomer, Dolors, additional, Villamor, Neus, additional, Aymerich, Marta, additional, Rozman, María, additional, Bayes, Mónica, additional, Gut, Marta, additional, Gelpí, Josep L, additional, Orozco, Modesto, additional, Fan, Jian-Bing, additional, Quesada, Víctor, additional, Puente, Xose S, additional, Pisano, David G, additional, Valencia, Alfonso, additional, López-Guillermo, Armando, additional, Gut, Ivo, additional, López-Otín, Carlos, additional, Campo, Elías, additional, and Martín-Subero, José I, additional

Published
2012
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152. Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features

Author

Navarro, Alba, primary, Clot, Guillem, additional, Royo, Cristina, additional, Jares, Pedro, additional, Hadzidimitriou, Anastasia, additional, Agathangelidis, Andreas, additional, Bikos, Vasilis, additional, Darzentas, Nikos, additional, Papadaki, Theodora, additional, Salaverria, Itziar, additional, Pinyol, Magda, additional, Puig, Xavier, additional, Palomero, Jara, additional, Vegliante, Maria Carmela, additional, Amador, Virgina, additional, Martinez-Trillos, Alejandra, additional, Stefancikova, Lenka, additional, Wiestner, Adrian, additional, Wilson, Wyndham, additional, Pott, Christiane, additional, Calasanz, Maria Jose, additional, Trim, Nicola, additional, Erber, Wendy, additional, Sander, Birgitta, additional, Ott, German, additional, Rosenwald, Andreas, additional, Colomer, Dolors, additional, Giné, Eva, additional, Siebert, Reiner, additional, Lopez-Guillermo, Armando, additional, Stamatopoulos, Kostas, additional, Beà, Sílvia, additional, and Campo, Elías, additional

Published
2012
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154. Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy.

Author

Alonso-Espinaco, Virginia, primary, Marmol, Maribel, additional, Alonso, Vicente, additional, Escudero, Pilar, additional, Horndler, Carlos, additional, Ortego, Javier, additional, Gallego, Rosa, additional, Garcia-Albeniz, Xabier, additional, Jares, Pedro, additional, Cuatrecasas, Miriam, additional, Lozano, Juan Jose, additional, Castells, Antoni, additional, and Maurel, Joan, additional

Published
2012
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155. Incidence and patterns of phospho insulin growth factor receptor-1 (pIGF-1R) and matrilysin (MMP7) expression in metastatic colorectal cancer (mCRC), and correlation with KRAS status: A prospective evaluation in the PULSE trial—A GEMCAD study.

Author

Alonso, Vicente, primary, Fernandez-Martos, Carlos, additional, Martin, Marta, additional, Salud, Antonieta, additional, Mendez, Jose Carlos, additional, Pericay, Carles, additional, Manzano, Hermini, additional, Gallego, Javier, additional, Horndler, Carlos, additional, Machado, Isidro, additional, Tobeña, Maria, additional, Garcia-Albeniz, Xabier, additional, Rubini, Michele, additional, Jares, Pedro, additional, Cuatrecasas, Miriam, additional, and Maurel, Joan, additional

Published
2012
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156. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia

Author

Quesada, Víctor, primary, Conde, Laura, additional, Villamor, Neus, additional, Ordóñez, Gonzalo R, additional, Jares, Pedro, additional, Bassaganyas, Laia, additional, Ramsay, Andrew J, additional, Beà, Sílvia, additional, Pinyol, Magda, additional, Martínez-Trillos, Alejandra, additional, López-Guerra, Mónica, additional, Colomer, Dolors, additional, Navarro, Alba, additional, Baumann, Tycho, additional, Aymerich, Marta, additional, Rozman, María, additional, Delgado, Julio, additional, Giné, Eva, additional, Hernández, Jesús M, additional, González-Díaz, Marcos, additional, Puente, Diana A, additional, Velasco, Gloria, additional, Freije, José M P, additional, Tubío, José M C, additional, Royo, Romina, additional, Gelpí, Josep L, additional, Orozco, Modesto, additional, Pisano, David G, additional, Zamora, Jorge, additional, Vázquez, Miguel, additional, Valencia, Alfonso, additional, Himmelbauer, Heinz, additional, Bayés, Mónica, additional, Heath, Simon, additional, Gut, Marta, additional, Gut, Ivo, additional, Estivill, Xavier, additional, López-Guillermo, Armando, additional, Puente, Xose S, additional, Campo, Elías, additional, and López-Otín, Carlos, additional

Published
2011
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157. 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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159. Applicability of Different Immunohistochemistry Algorithms to Assess Gene Expression Profile In Patients with Diffuse Large B-Cell Lymphoma

Author

Gutierrez-Garcia, Gonzalo, primary, Cardesa, Teresa, additional, Colomo, Luis, additional, Climent, Fina, additional, Mercadal, Santiago, additional, Mate, Jose Luis, additional, Sancho, Juan Manuel, additional, Escoda, Lourdes, additional, Serrano, Sergi, additional, Martinez, Antonio, additional, Jares, Pedro, additional, Garcia-Herrera, Adriana, additional, Martinez-Trillos, Alejandra, additional, Abrisqueta, Pau, additional, Pinyol, Magdalena, additional, Valera, Alexandra, additional, Arenillas, Leonor, additional, Gine, Eva, additional, Villamor, Neus, additional, Bosch, Francesc, additional, Campo, Elias, additional, and Lopez-Guillermo, Armando, additional

Published
2010
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160. Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma

Author

Fernàndez, Verònica, primary, Salamero, Olga, additional, Espinet, Blanca, additional, Solé, Francesc, additional, Royo, Cristina, additional, Navarro, Alba, additional, Camacho, Francisca, additional, Beà, Sílvia, additional, Hartmann, Elena, additional, Amador, Virginia, additional, Hernández, Luis, additional, Agostinelli, Claudio, additional, Sargent, Rachel L., additional, Rozman, Maria, additional, Aymerich, Marta, additional, Colomer, Dolors, additional, Villamor, Neus, additional, Swerdlow, Steven H., additional, Pileri, Stefano A., additional, Bosch, Francesc, additional, Piris, Miguel A., additional, Montserrat, Emili, additional, Ott, German, additional, Rosenwald, Andreas, additional, López-Guillermo, Armando, additional, Jares, Pedro, additional, Serrano, Sergi, additional, and Campo, Elías, additional

Published
2010
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161. Alteracions del control del cicle cel·lular en neoplàsies humanes

Author

Pinyol, Magda, Jares, Pedro, Nadal, Alfons, Campo Güerri, Elías, Hernández, Sílvia, Rey, M. Jesús, L. Fernández, Pedro, Cardesa García, Antonio, Cazorla, Maite, Pinyol, Magda, Jares, Pedro, Nadal, Alfons, Campo Güerri, Elías, Hernández, Sílvia, Rey, M. Jesús, L. Fernández, Pedro, Cardesa García, Antonio, and Cazorla, Maite

Published
2002

163. Chronic Lymphocytic Leukemia Apoptotic Cell Death Induced by Glucocorticoids Is Mediated by BIM and GILZ and Can Be Predicted by FKBP5 Basal Expression Levels.

Author

Baptista, Maria Joao, primary, Muntañola, Ana, additional, Codony, Carles, additional, Calpe, Eva, additional, Fernandez, Eva, additional, Crespo, Marta, additional, Abrisqueta, Pau, additional, Gine, Eva, additional, Kalko, Susana G, additional, Jares, Pedro, additional, Montserrat, Emili, additional, and Bosch, Francesc, additional

Published
2009
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164. MicroRNA Expression, Chromosomal Alterations, and Immunoglobulin Variable Heavy Chain Hypermutations in Mantle Cell Lymphomas

Author

Navarro, Alba, primary, Beà, Sílvia, additional, Fernández, Verónica, additional, Prieto, Miriam, additional, Salaverria, Itziar, additional, Jares, Pedro, additional, Hartmann, Elena, additional, Mozos, Anna, additional, López-Guillermo, Armando, additional, Villamor, Neus, additional, Colomer, Dolors, additional, Puig, Xavier, additional, Ott, German, additional, Solé, Francesc, additional, Serrano, Sergi, additional, Rosenwald, Andreas, additional, Campo, Elías, additional, and Hernández, Luis, additional

Published
2009
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165. 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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166. Molecular Signatures Implicate Innate Immune Cells, Fibrosis, and Angiogenesis in Survival Following R-CHOP Treatment of Diffuse Large B Cell Lymphoma

Author

Lenz, Georg, primary, Wright, George, primary, Dave, Sandeep, primary, Xiao, Wenming, primary, Powell, John, primary, Zhao, Hong, primary, Xu, Weihong, primary, Tan, Bruce, primary, Goldschmidt, Neta, primary, Iqbal, Javeed, primary, Vose, Julie, primary, Bast, Martin A, primary, Fu, Kai, primary, Weisenburger, Dennis D., primary, Greiner, Timothy C., primary, Armitage, James O., primary, Kyle, Alastair, primary, May, Lorraine, primary, Gascoyne, Randy D., primary, Connors, Joseph M., primary, Troen, Gunhild, primary, Holte, Harald, primary, Kvaloy, Stein, primary, Dierickx, Daan, primary, Verhoef, Gregor, primary, Delabie, Jan, primary, Smeland, Erlend B., primary, Jares, Pedro, primary, Martinez, Antonio, primary, Lopez-Guillermo, Armando, primary, Montserrat, Emili, primary, Campo, Elias, primary, Braziel, Rita M., primary, Miller, Thomas P., primary, Rimsza, Lisa M., primary, Cook, James R., primary, Pohlman, Brad, primary, Sweetenham, John William, primary, Tubbs, Raymond R., primary, Fisher, Richard I., primary, Hartmann, Elena, primary, Rosenwald, Andreas, primary, Ott, German, primary, Muller-Hermelink, Hans- Konrad, primary, Wrench, David, primary, Lister, T. Andrew, primary, Jaffe, Elaine S., primary, Wilson, Wyndham, primary, Chan, Wing C., primary, and Staudt, Louis M., primary

Published
2008
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167. Molecular Markers Predicting Clinical Outcome in Patients with Intermediate-Risk Acute Myeloid Leukemia Receiving Autologous Stem Cell Transplantation.

Author

Esteve, Jordi, primary, Kalko, Susana, additional, Torrebadell, Montserrat, additional, Camos, Mireia, additional, Jares, Pedro, additional, Rozman, Maria, additional, Pratcorona, Marta, additional, Brunet, Salut, additional, Nomdedeu, Josep, additional, Carrio, Ana, additional, Costa, Dolors, additional, and Montserrat, Emili, additional

Published
2007
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168. Gene Expression Signatures Predict Overall Survial in Diffuse Large B Cell Lymphoma Treated with Rituximab and Chop-Like Chemotherapy.

Author

Lenz, Georg, primary, Wright, George, additional, Dave, Sandeep, additional, Kohlmann, Alexander, additional, Xiao, Wenming, additional, Powell, John, additional, Zhao, Hong, additional, Xu, Weihong, additional, Gascoyne, Randy D., additional, Connors, Joseph M., additional, May, Lorraine, additional, Weisenburger, Dennis D., additional, Greiner, Tim, additional, Vose, Julie, additional, Armitage, James O., additional, Iqbal, Javeed, additional, Bast, Martin, additional, Fu, Kai, additional, Campo, Elias, additional, Montserrat, Emili, additional, Lopez-Guillermo, Armando, additional, Jares, Pedro, additional, Martinez, Antonio, additional, Gibbs, Betty, additional, Rimsza, Lisa M., additional, Fisher, Richard I., additional, Braziel, Rita M., additional, Tubbs, Ray, additional, Cook, James, additional, Pohlman, Brad, additional, Sweetenham, John, additional, Troen, Gunhild, additional, Smeland, Erlend B., additional, Delabie, Jan, additional, Kvaloy, Stein, additional, Holte, Harald, additional, Jaffe, Elaine S., additional, Wilson, Wyndham H., additional, Grant, Nicole, additional, Hartmann, Elena, additional, Rosenwald, Andreas, additional, Ott, German, additional, Muller-Hermelink, Hans-Konrad, additional, Lister, T. Andrew, additional, Williams, Mickey, additional, Wieczorek, Lothar, additional, Chan, Wing C., additional, and Staudt, Louis M., additional

Published
2007
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172. Gene Expression Profiling of Acute Myeloid Leukemia with Multilineage Dysplasia (AML-MD) Reveals a Biological Diversity Related to Underlying Cytogenetics but Also Identifies a Distinctive Profile in Normal Karyotype AML-MD.

Author

Rozman, María, primary, Kalko, Susana G., additional, Esteve, Jordi, additional, Camós, Mireia, additional, Aguilar, Josep-Lluís, additional, Torrebadell, Montserrat, additional, Costa, Dolors, additional, Carrió, Ana, additional, Jares, Pedro, additional, Montserrat, Emili, additional, and Campo, Elías, additional

Published
2006
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174. Gene Expression Profiling of Acute Myeloid Leukemia with Translocation t(8;16)(p11;p13) and MYST3-CREBBP Rearrangement Reveals a Distinctive Signature with a Specific Pattern of HOX Gene Expression

Author

Camós, Mireia, primary, Esteve, Jordi, additional, Jares, Pedro, additional, Colomer, Dolors, additional, Rozman, María, additional, Villamor, Neus, additional, Costa, Dolors, additional, Carrió, Ana, additional, Nomdedéu, Josep, additional, Montserrat, Emili, additional, and Campo, Elías, additional

Published
2006
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179. 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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181. p21WAF1/Cip1 is associated with cyclin D1CCND1 expression and tubular differentiation but is independent of p53 overexpression in human breast carcinoma

Author

Rey, Maria J., primary, Fernández, Pedro L., additional, Jares, Pedro, additional, Muñoz, Montserrat, additional, Nadal, Alfons, additional, Peiró, Nerea, additional, Nayach, Irazema, additional, Mallofré, Carmen, additional, Muntané, Jaume, additional, Campo, Elåffias, additional, Estapé, Jordi, additional, and Cardesa, Antonio, additional

Published
1998
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182. CYCLIN D1 AND RETINOBLASTOMA GENE EXPRESSION IN HUMAN BREAST CARCINOMA: CORRELATION WITH TUMOUR PROLIFERATION AND OESTROGEN RECEPTOR STATUS

Author

JARES, PEDRO, primary, REY, MARÍA J., additional, FERNÁNDEZ, PEDRO L., additional, CAMPO, ELÍAS, additional, NADAL, ALFONS, additional, MUÑOZ, MONTSERRAT, additional, MALLOFRÉ, CARMEN, additional, MUNTANÉ, JAUME, additional, NAYACH, IRACEMA, additional, ESTAPÉ, JORDI, additional, and CARDESA, ANTONIO, additional

Published
1997
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185. Detection of thebcl-1 Rearrangement at the Major Translocation Cluster in Frozen and Paraffin-Embedded Tissues of Mantle Cell Lymphomas by Polymerase Chain Reaction

Author

Pinyol, Magda, primary, Campo, Elías, additional, Nadal, Alfons, additional, Terol, Maria José, additional, Jares, Pedro, additional, Nayach, Irazema, additional, Fernandez, Pedro L., additional, Angel Piris, Miguel, additional, Montserrat, Emilio, additional, and Cardesa, Antonio, additional

Published
1996
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186. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma.

Author

Beà, Sílvia, Valdés-Mas, Rafael, Navarro, Alba, Salaverria, Itziar, Martín-Garcia, David, Jares, Pedro, Giné, Eva, Pinyol, Magda, Royo, Cristina, Nadeu, Ferran, Conde, Laura, Juan, Manel, Clot, Guillem, Vizán, Pedro, Di Croce, Luciano, Puente, Diana A., López-Guerra, Mónica, Moros, Alexandra, Roue, Gael, and Aymerich, Marta

Subjects
LYMPHOMAS, CELL tumors, GENETIC mutation, CLONE cells, DNA, CELL lines, TUMOR suppressor genes
Abstract

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Published
2013
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187. Next-generation sequencing reveals the secrets of the chronic lymphocytic leukemia genome.

Author

Ramsay, Andrew, Martínez-Trillos, Alejandra, Jares, Pedro, Rodríguez, David, Kwarciak, Agnieszka, and Quesada, Víctor

Abstract

The study of the detailed molecular history of cancer development is one of the most promising techniques to understand and fight this diverse and prevalent disease. Unfortunately, this history is as diverse as cancer itself. Therefore, even with next-generation sequencing techniques, it is not easy to distinguish significant (driver) from random (passenger) events. The International Cancer Genome Consortium (ICGC) was formed to solve this fundamental issue by coordinating the sequencing of samples from 50 different cancer types and/or sub-types that are of clinical and societal importance. The contribution of Spain in this consortium has been focused on chronic lymphocytic leukemia (CLL). This approach has unveiled new and unexpected events in the development of CLL. In this review, we introduce the approaches utilized by the consortium for the study of the CLL genome and discuss the recent results and future perspectives of this work. [ABSTRACT FROM AUTHOR]

Published
2013
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188. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.

Author

Quesada, Víctor, Conde, Laura, Villamor, Neus, Ordóñez, Gonzalo R, Jares, Pedro, Bassaganyas, Laia, Ramsay, Andrew J, Beà, Sílvia, Pinyol, Magda, Martínez-Trillos, Alejandra, López-Guerra, Mónica, Colomer, Dolors, Navarro, Alba, Baumann, Tycho, Aymerich, Marta, Rozman, María, Delgado, Julio, Giné, Eva, Hernández, Jesús M, and González-Díaz, Marcos

Subjects
CHRONIC lymphocytic leukemia, B cells, RNA splicing, GENE expression, TOLL-like receptors, MOLECULAR structure of chromatin, NUCLEOPROTEINS, DISEASES
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. [ABSTRACT FROM AUTHOR]

Published
2012
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189. Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review.

Author

Ribera-Cortada, Inmaculada, Guerrero-Pineda, José, Trias, Isabel, Veloza, Luis, Garcia, Adriana, Marimon, Lorena, Diaz-Mercedes, Sherley, Alamo, José Ramon, Rodrigo-Calvo, Maria Teresa, Vega, Naiara, López del Campo, Ricardo, Parra-Medina, Rafael, Ajami, Tarek, Martínez, Antonio, Reig, Oscar, Ribal, Maria J., Corral-Molina, Juan Manuel, Jares, Pedro, Ordi, Jaume, and Rakislova, Natalia

Subjects
SQUAMOUS cell carcinoma, PAPILLOMAVIRUS diseases, DNA copy number variations, PENILE erection, DNA sequencing
Abstract

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC. [ABSTRACT FROM AUTHOR]

Published
2022
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190. SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

Author

Palomero, Jara, Vegliante, Maria Carmela, Rodríguez, Marta Leonor, Eguileor, Álvaro, Castellano, Giancarlo, Planas-Rigol, Ester, Jares, Pedro, Ribera-Cortada, Inmaculada, Cid, Maria C., Campo, Elias, and Amador, Virginia

Abstract

SOX11 is overexpressed in several solid tumors and in the vast majority of aggressive mantle cell lymphomas (MCLs). We have recently proven that SOX11 silencing reduces tumor growth in a MCL xenograft model, consistent with the indolent clinical course of the human SOX11-negative mantle cell lymphoma (MCL). However, the direct oncogenic mechanisms and downstream effector pathways implicated in SOX11-driven transformation remain poorly understood. Here, we observed that SOX11-positive xenograft and human primary MCL tumors overexpressed angiogenic gene signatures and had a higher microvascular density compared with their SOX11-negative counterparts. Conditioned media of SOX11-positive MCL cell lines induced in vitro endothelial cell proliferation, migration, tube formation, and activation of downstream angiogenic pathways. We identified PDGFA as a SOX11 direct target gene upregulated in MCL cells whose inhibition impaired SOX11-enhanced in vitro angiogenic effects on endothelial cells. In addition, platelet-derived growth factor A (PDGFA) was overexpressed in SOX11-positive but not in SOX11-negative MCL. In vivo, imatinib impaired tumor angiogenesis and lymphoma growth in SOX11-positive MCL xenograft tumors. Overall, our results demonstrate a prominent role for SOX11 as a driver of proangiogenic signals in MCL, and highlight the SOX11-PDGFA axis as a potential therapeutic target for the treatment of this aggressive disease.

Published
2014
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191. Mutations in TLR/MYD88pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome

Author

Martínez-Trillos, Alejandra, Pinyol, Magda, Navarro, Alba, Aymerich, Marta, Jares, Pedro, Juan, Manel, Rozman, María, Colomer, Dolors, Delgado, Julio, Giné, Eva, González-Díaz, Marcos, Hernández-Rivas, Jesús M., Colado, Enrique, Rayón, Consolación, Payer, Angel R., Terol, Maria José, Navarro, Blanca, Quesada, Victor, Puente, Xosé S., Rozman, Ciril, López-Otín, Carlos, Campo, Elías, López-Guillermo, Armando, and Villamor, Neus

Abstract

Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88(one with concurrent IRAK1mutation), 2 TLR2(one with concomitant TLR6mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88mutations were the most frequent in young patients. Patients with mutated TLR/MYD88CLL had a higher frequency of mutated IGHVand low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P= .002), and in the subset of patients age ≤50 years (100% vs 70%; P= .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88mutations identify a population of young CLL patients with favorable outcome.

Published
2014
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192. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma

Author

Vegliante, Maria Carmela, Palomero, Jara, Pérez-Galán, Patricia, Roué, Gaël, Castellano, Giancarlo, Navarro, Alba, Clot, Guillem, Moros, Alexandra, Suárez-Cisneros, Helena, Beà, Sílvia, Hernández, Luis, Enjuanes, Anna, Jares, Pedro, Villamor, Neus, Colomer, Dolors, Martín-Subero, José Ignacio, Campo, Elias, and Amador, Virginia

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 chromatin immunoprecipitation microarray 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. PAX5emerges 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 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.

Published
2013
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193. Disregulation of p16.

Author

Jares, Pedro, Nadal,, Alfons, Fernández, Pedro L., Pinyol, Magda, Hernández, Lluis, Cazorla, Maite, Hernández, Silvia, Beà, Silvia, Cardesa, Antonio, and Campo, Elías

Published
1999
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194. The Expression of the Endoplasmic Reticulum Stress Sensor BiP/GRP78 Predicts Response to Chemotherapy and Determines the Efficacy of Proteasome Inhibitors in Diffuse Large B-Cell Lymphoma

Author

Mozos, Ana, Roué, Gaël, López-Guillermo, Armando, Jares, Pedro, Campo, Elias, Colomer, Dolors, and Martinez, Antonio

Abstract

Activation of the endoplasmic reticulum (ER) stress pathway is associated with poor response to doxorubicin-containing regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone (R-CHOP), in patients with diffuse large B-cell lymphoma (DLBCL). Bortezomib, a proteasome inhibitor, interferes with ER responses and improves survival in patients with aggressive hematologic malignant tumors, although its use in DLBCL patients remains controversial. The 78-kDa glucose-regulated protein (GRP78), also known as immunoglobulin heavy chain binding protein (BiP), is an ER stress sensor involved in the resistance to doxorubicin and bortezomib, but its role in the response to chemotherapy in DLBCL has not been explored before. We show that high BiP/GRP78 expression is related to worse overall survival (median overall survival, 5.2 versus 3.4 years). Moreover, cell death after R-CHOP in DLCBL cell lines is associated with decreased BiP/GRP78 expression. Conversely, DLBCL cell lines are primarily resistant to bortezomib, probably owing to BiP/GRP78 overexpression. Small-interfering RNA silencing of BiP/GRP78 renders all cell lines sensitive to bortezomib. R-CHOP with bortezomib (R-CHOP-BZ) reduces BiP/GRP78 expression and overcomes bortezomib resistance, mimicking the small-interfering RNA silencing of BiP/GRP78. Accordingly, R-CHOP-BZ is the most effective treatment, providing a rationale for the use of this combinational therapy to improve DLBCL patient survival. Moreover, this study provides preclinical evidence that the germinal center B-cell–like subtype DLBCL is sensitive to bortezomib combined with immunochemotherapy.

Published
2011
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195. Molecular Pathogenesis of Mantle Cell Lymphoma: New Perspectives and Challenges With Clinical Implications

Author

Navarro, Alba, Royo, Cristina, Hernández, Luis, Jares, Pedro, and Campo, Elías

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.

Published
2011
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196. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Author

Gutiérrez-García, Gonzalo, Cardesa-Salzmann, Teresa, Climent, Fina, González-Barca, Eva, Mercadal, Santiago, Mate, José L., Sancho, Juan M., Arenillas, Leonor, Serrano, Sergi, Escoda, Lourdes, Martínez, Salomé, Valera, Alexandra, Martínez, Antonio, Jares, Pedro, Pinyol, Magdalena, García-Herrera, Adriana, Martínez-Trillos, Alejandra, Giné, Eva, Villamor, Neus, Campo, Elías, Colomo, Luis, and López-Guillermo, Armando

Abstract

Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell–like (GCB) and activated-B cell–like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.

Published
2011
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197. p16MTS1/CDK4I mutations and concomitant loss of heterozygosity at 9p21-23 are frequent events in squamous cell carcinoma of the larynx.

Author

Jares, Pedro, Fernández, Pedro L, Nadal, Alfons, Cazorla, Maite, Hernández, Lluís, Pinyol, Magda, Hernández, Silvia, Traserra, Jose, Cardesa, Antonio, and Campo, Elías

Subjects
*SQUAMOUS cell carcinoma, *LARYNGEAL cancer, *HETEROZYGOSITY, *ONCOGENES, *TUMORS
Abstract

We have examined the presence of p16MTS1/CDK4I gene deletions, mutations and methylation status, and 9p21-23 deletions in a series of 46 squamous cell carcinomas of the larynx and paired normal mucosa previously characterized for cyclin D1 gene amplification and overexpression. pRb expression was also examined by immunohistochemistry. p16MTS1/CDK4I mutations were found in 10/46 (22%) carcinomas and hypermethylation in 2/31 (7%). Loss of heterozygosity at 9p21-23 was found in 24 out of 42 (57%) carcinomas examined. All p16MTS1/CDK4I mutated cases and the two hypermethylated carcinomas showed 9p21-23 loss of heterozygosity. The loss of heterozygosity correlated with advanced local invasion (P=0.0045), lymph node metastases (P=0.0326), stage IV of the tumors (P=0.0058), and existence of cyclin D1 amplification/overexpression (P<0.03). Only one out of 37 carcinomas was negative for pRb expression. No alterations in p16 gene or 9p21-23 loss of heterozygosity were detected in this case. These findings indicate that p16MTS1/CDK4I is frequently inactivated by gene mutation, hypermethylation, and allelic deletions in a significant subset of squamous cell carcinomas of larynx. Since 9p21-23 loss of heterozygosity was more frequently detected than p16MTS1/CDK4I mutations, and mutated carcinomas invariably had loss of heterozygosity, allelic losses probably precede the p16MTS1/CDK4I mutations. Their association with cyclin D1 deregulation in advanced carcinomas could indicate a possible cooperative effect in the progression of these neoplasms. [ABSTRACT FROM AUTHOR]

Published
1997
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200. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling

Author

Hartmann, Elena M., Campo, Elias, Wright, George, Lenz, Georg, Salaverria, Itziar, Jares, Pedro, Xiao, Wenming, Braziel, Rita M., Rimsza, Lisa M., Chan, Wing-Chung, Weisenburger, Dennis D., Delabie, Jan, Jaffe, Elaine S., Gascoyne, Randy D., Dave, Sandeep S., Mueller-Hermelink, Hans-Konrad, Staudt, Louis M., Ott, German, Beà, Sílvia, and Rosenwald, Andreas

Abstract

The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2Alocus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2was associated with inferior outcome, including an independent validation series of 32 MCLs.

Published
2010
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