128 results on '"Nadeu, F"'
Search Results
2. Signatures of TOP1 transcription-associated mutagenesis in cancer and germline
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Reijns M. A. M., Parry D. A., Williams T. C., Nadeu F., Hindshaw R. L., Rios Szwed D. O., Nicholson M. D., Carroll P., Boyle S., Royo R., Cornish A. J., Xiang H., Ridout K., Schuh A., Caravagna G, Aden K., Palles C., Campo E., Stankovic T., Taylor M. S., Jackson A. P., Barcelona Supercomputing Center, Reijns, M. A. M., Parry, D. A., Williams, T. C., Nadeu, F., Hindshaw, R. L., Rios Szwed, D. O., Nicholson, M. D., Carroll, P., Boyle, S., Royo, R., Cornish, A. J., Xiang, H., Ridout, K., Schuh, A., Caravagna, G, Aden, K., Palles, C., Campo, E., Stankovic, T., Taylor, M. S., and Jackson, A. P.
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Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC] ,Genomic instability ,cancer genomics ,Eukaryotic cells ,Nucleotide excision repair ,Multidisciplinary ,Cancer genomics ,Genomes ,Càncer--Aspectes genètics - Abstract
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome. We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Peer Reviewed "Article signat per 22 autors/es: Martin A. M. Reijns, David A. Parry, Thomas C. Williams, Ferran Nadeu, Rebecca L. Hindshaw, Diana O. Rios Szwed, Michael D. Nicholson, Paula Carroll, Shelagh Boyle, Romina Royo, Alex J. Cornish, Hang Xiang, Kate Ridout, The Genomics England Research Consortium, Colorectal Cancer Domain UK 100,000 Genomes Project, Anna Schuh, Konrad Aden, Claire Palles, Elias Campo, Tatjana Stankovic, Martin S. Taylor & Andrew P. Jackson "
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- 2022
3. P631: A PCR-BASED ASSAY FOR IGLV3-21R110 SCREENING CONFIRMS ITS PROGNOSTIC VALUE IN AN INDEPENDENT COHORT OF 613 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA.
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Syrykh, C., primary, Russiñol, N., additional, Baumann, T., additional, Kulis, M., additional, Alcoceba, M., additional, González, M., additional, Colado, E., additional, Payer, Á. R., additional, Aymerich, M., additional, Terol, M. J., additional, Ruiz-Gaspà, S., additional, López-Guillermo, A., additional, Martín-Subero, J. I., additional, Colomer, D., additional, Delgado, J., additional, Campo, E., additional, and Nadeu, F., additional
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- 2022
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4. P1295: DECIPHERING THE ROLE OF MSI2 AS A REGULATOR OF MANTLE CELL LYMPHOMA STEM-LIKE PROPERTIES
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Sureda-Gómez, M., primary, Balsas, P., additional, Rodríguez, M.-L., additional, Nadeu, F., additional, De Bolòs, A., additional, Eguileor, Á., additional, Kulis, M., additional, Castellano, G., additional, Giné, E., additional, Demajo, S., additional, Martín-Subero, J. I., additional, Jares, P., additional, Campo, E., additional, and Amador, V., additional
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- 2022
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5. P1260: UNRAVELING THE GENETICS OF TRANSFORMED SPLENIC MARGINAL ZONE LYMPHOMA
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Grau, M., primary, López, C., additional, Navarro, A., additional, Clot, G., additional, Nadeu, F., additional, Bastidas, G., additional, Alcoceba, M., additional, Baptista, M. J., additional, Blanes, M., additional, Climent, F., additional, Colomer, D., additional, Costa, D., additional, Domingo-Domènech, E., additional, Forcada, P., additional, Enjuanes, A., additional, Escoda, L., additional, Frigola, G., additional, Giné, E., additional, Lopez-Guerra, M., additional, Rivas-Delgado, A., additional, Vicente-Folch, L., additional, Wotherspoon, A., additional, Campo, E., additional, López-Guillermo, A., additional, Matutes, E., additional, and Beà, S., additional
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- 2022
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6. P1282: DISEASE-SPECIFIC U1 SPLICEOSOMAL RNA MUTATIONS IN MATURE B-CELL NEOPLASMS
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Nadeu, F., primary, Shuai, S., additional, Clot, G., additional, Hilton, L. K., additional, Diaz-Navarro, A., additional, Martín, S., additional, Royo, R., additional, Baumann, T., additional, Kulis, M., additional, López-Oreja, I., additional, Cossio, M., additional, Lu, J., additional, Ljungström, V., additional, Young, E., additional, Plevova, K., additional, Knisbacher, B. A., additional, Lin, Z., additional, Hahn, C. K., additional, Bousquets, P., additional, Alcoceba, M., additional, González, M., additional, Colado, E., additional, Aymerich, M., additional, Terol, M. J., additional, Rivas-Delgado, A., additional, Enjuanes, A., additional, Ruiz-Gaspà, S., additional, Chatzikonstantinou, T., additional, Hägerstrand, D., additional, Jylhä, C., additional, Skaftason, A., additional, Mansouri, L., additional, Stranska, K., additional, Doubek, M., additional, van Gastel-Mol, E. J., additional, Davis, Z., additional, Walewska, R., additional, Scarfò, L., additional, Trentin, L., additional, Visentin, A., additional, Parikh, S. A., additional, Rabe, K. G., additional, Moia, R., additional, Armand, M., additional, Rossi, D., additional, Davi, F., additional, Gaidano, G., additional, Kay, N. E., additional, Shanafelt, T., additional, Ghia, P., additional, Oscier, D., additional, Langerak, A. W., additional, Beà, S., additional, López-Guillermo, A., additional, Neuberg, D., additional, Wu, C. J., additional, Getz, G., additional, Pospisilova, S., additional, Stamatopoulos, K., additional, Rosenquist, R., additional, Huber, W., additional, Zenz, T., additional, Colomer, D., additional, Martín-Subero, J. I., additional, Delgado, J., additional, Morin, R. D., additional, Stein, L. D., additional, Puente, X. S., additional, and Campo, E., additional
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- 2022
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7. P1277: MUTATIONAL LANDSCAPE AND COPY NUMBER ALTERATIONS IN TESTICULAR LARGE B-CELL LYMPHOMA
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López, C., primary, Rivas-Delgado, A., additional, Nadeu, F., additional, Grau, M., additional, Rivero, A., additional, Boschs-Schips, J., additional, Alcoceba, M., additional, Tapia, G., additional, Luizaga, L., additional, Bárcena, C., additional, Kelleher, N., additional, Pablo, M., additional, Balague, O., additional, Frigola, G., additional, Villamor, N., additional, Magnano, L., additional, Baumann, T., additional, Muntañola, A., additional, Sancho-Cia, J. M., additional, García-Sancho, A. M., additional, Gonzalez Barca, E., additional, Climent, F., additional, Campo, E., additional, Giné, E., additional, López-Guillermo, A., additional, and Beà, S., additional
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- 2022
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8. FIVE‐YEAR UPDATE OF THE FIRST‐LINE IMCL‐2015 GELTAMO STUDY. PROLONGED MOLECULAR AND CLINICAL RESPONSES WERE OBSERVED AFTER MRD‐DRIVEN IBRUTINIB DISCONTINUATION.
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Giné, E., Medina‐Herrera, A., Cruz, F. de la, Ubieto, A. Jiménez, Jiménez, J. López, García‐ Sancho, A. Martín, Terol, M J., Barca, E. González, Casanova, M., Fuente, A. de la, Niebla, A. Marín, Muntañola, A., López, T. J. González, Aymerich, M., Setoain, X., Cortés‐Romera, M., Rotger, A., Rodríguez, S., López, C., and Nadeu, F.
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MANTLE cell lymphoma - Abstract
B Conclusions: b An MRD-driven strategy allows ibrutinib discontinuation in indolent clinical forms of MCL patients who persist with prolonged MRD and also clinical responses. At current follow-up, 6 patients remain on treatment, and up to 13 patients discontinued ibrutinib because of adverse events, including 7 associated to ibrutinib with a hemorrhagic cardiac tamponade being the most severe. [Extracted from the article]
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- 2023
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9. TESTICULAR LARGE B‐CELL LYMPHOMA IS GENETICALLY SIMILAR TO PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA AND DISTINCT FROM NODAL DIFFUSE LARGE B‐CELL LYMPHOMA.
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Rivas‐Delgado, A., López, C., Clot, G., Nadeu, F., Grau, M., Frigola, G., Bosch, J., Radke, J., Ishaque, N., Alcoceba, M., Melendo, G. Tapia, Luizaga, L., Barcena, C., Kelleher, N., Villamor, N., Baumann, T., Muntañola, A., Sancho‐Cia, J. M., García‐Sancho, A. Martin, and Gonzalez‐Barca, E.
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DIFFUSE large B-cell lymphomas ,CENTRAL nervous system ,LYMPHOMAS - Abstract
TESTICULAR LARGE B-CELL LYMPHOMA IS GENETICALLY SIMILAR TO PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA AND DISTINCT FROM NODAL DIFFUSE LARGE B-CELL LYMPHOMA B Introduction: b Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma presenting in an immune-privileged site, recently recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). Compared with nodal DLBCL, localized and disseminated TLBCL have less CNA complexity ( I P i = 0.01 and I P i < 0.04, respectively) but showed a higher number of variants ( I P i = 0.01 and I P i < 0.001, respectively). [Extracted from the article]
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- 2023
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10. A SIMPLE EPIGENETIC SIGNATURE DEFINES TWO BIOLOGIC GROUPS OF MANTLE CELL LYMPHOMA
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Bühler, M. M., primary, Kulis, M., additional, Duran‐Ferrer, M., additional, Clot, G., additional, Nadeu, F., additional, Navarro, A., additional, López, C., additional, Giné, E., additional, Beà, S., additional, Campo, E., additional, and Martín‐Subero, J. I., additional
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- 2021
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11. TESTICULAR DIFFUSE LARGE B‐CELL LYMPHOMA: CLINICO‐BIOLOGICAL CHARACTERIZATION, EVALUATION OF TREATMENT RESPONSE AND SURVIVAL
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Rivas‐Delgado, A., primary, López, C., additional, Nadeu, F., additional, Grau, M., additional, Rivero, A., additional, Bosch, J., additional, Alcoceba, M., additional, Gustavo, T., additional, Luizaga, L., additional, Barcena, C., additional, Kelleher, N., additional, Martin, S., additional, Mozas, P., additional, Balague, O., additional, Frigola, G., additional, Magnano, L., additional, Baumann, T., additional, Villamor, N., additional, Muntañola, A., additional, Sancho, J. M., additional, García‐Sancho, A. Martin, additional, Gonzalez‐Barca, E., additional, Climent, F., additional, Campo, E., additional, Giné, E., additional, López‐Guillermo, A., additional, and Beà, S., additional
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- 2021
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12. IRF4-rearranged Large B-cell lymphoma (LBCL) has a genomic profile distinct to other LBCL in children and young adults
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Ramis-Zaldivar JE, Gonzalez-Farre B, Balagué O, Celis V, Nadeu F, Salmeron-Villalobos J, Andres M, Martin-Guerrero I, Garrido-Pontnou M, Gaafar A, Suñol M, Barcena C, Garcia-Bragado F, Andión M, Azorín D, Astigarraga I, Sagaseta de Ilurdoz M, Sábado C, Gallego S, Verdu-Amorós J, Fernandez-Delgado R, Perez V, Tapia G, Mozos A, Torrent M, Solano-Páez P, Rivas-Delgado A, Dlouhy I, Clot G, Enjuanes A, López-Guillermo A, Galera PK, Oberley MJ, Maguire A, Ramsower C, Rimsza LM, Quintanilla-Martinez L, Jaffe ES, Campo E, and Salaverria I
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GENOME ,MUTATIONS ,PATHOGENESIS ,CHILDREN ,BURKITT-LYMPHOMA ,FREQUENT ,FOLLICULAR LYMPHOMA ,HIGH-RESOLUTION ,CLASSIFICATION ,GENE-EXPRESSION - Abstract
Pediatric large B-cell lymphomas (LBCL) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children, suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse large B-cell lymphomas, not otherwise specified (DLBCL, NOS), 20 LBCL-IRF4, and 12 high grade B-cell lymphomas, NOS (HGBCL, NOS) in patients {less than or equal to}25 years-old using an integrated approach including targeted gene sequencing, copy number arrays and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-kB pathway genes (CARD11, CD79B and MYD88), losses of 17p13 and gains of chr7, 11q12.3-q25 whereas DLBCL,NOS were predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (e.g. SOCS1 and KMT2D), gains of 2p16/REL and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma related genes such as MYC, ID3 and DDX3X and homozygous deletions of 9p21/CDKN2A whereas other cases were genetically closer to GCB-DLBCL. Factors related to unfavorable outcome were age >18y old, activated B-cell DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric/young-adult LBCL, improve the classification of this group of tumors and provide new parameters for risk stratification.
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- 2020
13. Cryptic insertions of the immunoglobulin light chain enhancer region near CCND1 in t(11;14)-negative mantle cell lymphoma
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Fuster C, Martin-Garcia D, Balague O, Navarro A, Nadeu F, Costa D, Prieto M, Salaverria I, Espinet B, Rivas-Delgado A, Terol M, Gine E, Forcada P, Ashton-Key M, Puente X, Swerdlow S, Bea S, and Campo E
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- 2020
14. 064 - SOX11 AND EPSTEIN–BARR VIRUS MAY SUBSTITUTE EACH OTHER IN EARLY PATHOGENESIS OF BURKITT LYMPHOMA
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Sureda-Gómez, M., Iaccarino, I., Balsas, P., Richter, J., Glaser, S., Rodríguez, M., De Bolòs, A., Nadeu, F., Campo, E., Siciliano, M., Leoncini, L., Siebert, R., Klapper, W., and Amador, V.
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- 2022
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15. Life expectancy of follicular lymphoma patients in complete response at 30 months is similar to that of the Spanish general population
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Magnano L, Alonso-Alvarez S, Alcoceba M, Rivas-Delgado A, Muntanola A, Nadeu F, Setoain X, Rodriguez S, Andrade-Campos M, Espinosa-Lara N, Rodriguez G, Sancho J, Moreno M, Mercadal S, Carro I, Salar A, Garcia-Pallarols F, Arranz R, Cannata J, Terol M, Teruel A, Jimenez-Ubiet A, Rodrigue A, de Villambrosi S, Bell J, Lopez L, Novelli S, de Cabo E, Infante M, Pardal E, Monsalvo S, Gonzalez M, Martin A, Caballero M, Lopez-Guillermo A, and GELTAMO
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- 2019
16. MUTATIONAL LANDSCAPE OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) AT DIAGNOSIS AND AT PROGRESSION ASSESSED BY CIRCULATING TUMOR DNA ANALYSIS
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Rivas-Delgado, A., primary, Nadeu, F., additional, Enjuanes, A., additional, Magnano, L., additional, Castrejón de Anta, N., additional, Mozas, P., additional, Baumann, T., additional, Delgado, J., additional, Balagué, O., additional, Villamor, N., additional, Campo, E., additional, Giné, E., additional, and López-Guillermo, A., additional
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- 2019
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17. MUTATIONAL LANDSCAPE OF PRIMARY MEDIASTINAL B-CELL LYMPHOMA (PMBCL) BY MEANS OF CIRCULATING TUMOR DNA ANALYSIS
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Rivas-Delgado, A., primary, Nadeu, F., additional, Enjuanes, A., additional, Magnano, L., additional, Mozas, P., additional, Osuna, M., additional, Martín, S., additional, Baumann, T., additional, de Anta, Catrejon N., additional, Balague, O., additional, Delgado, J., additional, Villamor, N., additional, Campo, E., additional, Gine, E., additional, and Lopez-Guillermo, A., additional
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- 2019
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18. PF522 MUTATIONAL LANDSCAPE OF PRIMARY MEDIASTINAL B-CELL LYMPHOMA (PMBCL) BY MEANS OF CIRCULATING TUMOR DNA ANALYSIS
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Rivas-Delgado, A., primary, Nadeu, F., additional, Enjuanes, A., additional, Magnano, L., additional, Mozas, P., additional, Osuna, M., additional, Martín, S., additional, Baumann, T., additional, Catrejon de Anta, N., additional, Balague, O., additional, Delgado, J., additional, Villamor, N., additional, Campo, E., additional, Gine, E., additional, and Lopez-Guillermo, A., additional
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- 2019
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19. PATTERNS OF CHANGE IN TREATMENT, SURVIVAL, HISTOLOGICAL TRANSFORMATION, AND SECONDARY MALIGNANCIES OF FOLLICULAR LYMPHOMA OVER THE LAST 4 DECADES: A SINGLE CENTER EXPERIENCE
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Mozas, P., primary, Magnano, L., additional, Rivas-Delgado, A., additional, Rivero, A., additional, Nadeu, F., additional, Veloza, L., additional, González-Farré, B., additional, Baumann, T., additional, Balagué, O., additional, Giné, E., additional, Delgado, J., additional, Villamor, N., additional, Campo, E., additional, and López-Guillermo, A., additional
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- 2019
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20. S843 THE PROLIFERATIVE HISTORY SHAPES THE DNA METHYLOME OF B-CELL TUMORS AND PREDICTS CLINICAL OUTCOME
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Duran-Ferrer, M., primary, Clot, G., additional, Nadeu, F., additional, Beekman, R., additional, Baumann, T., additional, Nordlund, J., additional, Marincevic-Zuniga, Y., additional, Rivas-Delgado, A., additional, Ordoñez, R., additional, Castellano, G., additional, Kulis, M., additional, Queirós, A., additional, Seung-Tae, L., additional, Wiemels, J., additional, Royo, R., additional, Puiggrós, M., additional, Torrents, D., additional, Giné, E., additional, Beà, S., additional, Jares, P., additional, Agirre, X., additional, Prosper, F., additional, López-Otín, C., additional, Puente, X.S., additional, Delgado, J., additional, López-Guillermo, A., additional, Campo, E., additional, and Martín-Subero, J.I., additional
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- 2019
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21. PS1147 SPATIAL HETEROGENEITY IN CHRONIC LYMPHOCYTIC LEUKAEMIA ANALYSED BY WHOLE-GENOME/EXOME SEQUENCING AT DIAGNOSIS
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Nadeu, F., primary, Royo, R., additional, Maura, F., additional, Dawson, K.J., additional, Dueso, A., additional, Torrents, D., additional, Aymerich, M., additional, Pinyol, M., additional, Beà, S., additional, López-Guillermo, A., additional, Delgado, J., additional, Puente, X.S., additional, and Campo, E., additional
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- 2019
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22. GENOTYPING PRIMARY MEDIASTINAL B-CELL LYMPHOMA (PMBCL) BY MEANS OF CIRCULATING TUMOR DNA ANALYSIS
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Rivas-Delgado, A., primary, Nadeu, F., additional, Enjuanes, A., additional, Magnano, L., additional, Mozas, P., additional, Osuna, M., additional, Martín, S., additional, Baumann, T., additional, Castrejón de Anta, N., additional, Balagué, O., additional, Delgado, J., additional, Villamor, N., additional, Campo, E., additional, Giné, E., additional, and López-Guillermo, A., additional
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- 2019
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23. GENE MUTATIONS AND ALTERATIONS OF THE NUMBER OF COPIES PREDICT EARLY FAILURE IN PATIENTS WITH LARGE CELL DIFFUSE LYMPHOMA (LDCGB) TREATED WITH R-CHOP
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Dlouhy, I, Karube, K, Enjuanes, A, Salaverria, I, Jares, P, Garcia, DM, Nadeu, F, Delgado, AR, Galan, PP, Rovira, J, Gonzalez, B, Mozos, A, Clot, G, Sancho, JM, Salar, A, Mercadal, S, Escoda, L, Briones, J, Colomo, L, Alcoceba, M, Valera, A, Campo, E, and Guillermo, AL
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- 2017
24. Polyploidy and chromosomal instability correlates with proliferative traits and lack of immune-related gene signatures in hepatocellular carcinoma
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Bassaganyas, L., primary, Torrecilla, S., additional, Moeini, A., additional, Nadeu, F., additional, Sia, D., additional, Salaverria, I., additional, Cabellos, L., additional, Pinyol, R., additional, Camps, J., additional, Mazzaferro, V., additional, and Llovet, J.M., additional
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- 2018
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25. Clinical impact of the subclonal architecture and mutational complexity in chronic lymphocytic leukemia
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Nadeu, F, primary, Clot, G, additional, Delgado, J, additional, Martín-García, D, additional, Baumann, T, additional, Salaverria, I, additional, Beà, S, additional, Pinyol, M, additional, Jares, P, additional, Navarro, A, additional, Suárez-Cisneros, H, additional, Aymerich, M, additional, Rozman, M, additional, Villamor, N, additional, Colomer, D, additional, González, M, additional, Alcoceba, M, additional, Terol, M J, additional, Navarro, B, additional, Colado, E, additional, Payer, ÁR, additional, Puente, X S, additional, López-Otín, C, additional, López-Guillermo, A, additional, Enjuanes, A, additional, and Campo, E, additional
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- 2017
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26. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets
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Karube, K, primary, Enjuanes, A, additional, Dlouhy, I, additional, Jares, P, additional, Martin-Garcia, D, additional, Nadeu, F, additional, Ordóñez, G R, additional, Rovira, J, additional, Clot, G, additional, Royo, C, additional, Navarro, A, additional, Gonzalez-Farre, B, additional, Vaghefi, A, additional, Castellano, G, additional, Rubio-Perez, C, additional, Tamborero, D, additional, Briones, J, additional, Salar, A, additional, Sancho, J M, additional, Mercadal, S, additional, Gonzalez-Barca, E, additional, Escoda, L, additional, Miyoshi, H, additional, Ohshima, K, additional, Miyawaki, K, additional, Kato, K, additional, Akashi, K, additional, Mozos, A, additional, Colomo, L, additional, Alcoceba, M, additional, Valera, A, additional, Carrió, A, additional, Costa, D, additional, Lopez-Bigas, N, additional, Schmitz, R, additional, Staudt, L M, additional, Salaverria, I, additional, López-Guillermo, A, additional, and Campo, E, additional
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- 2017
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27. INTEGRATIVE MUTATIONAL ANALYSIS OF PEDIATRIC-TYPE FOLLICULAR LYMPHOMA REVEALS TNFRSF14 AND MAP2K1 AS THE MOST FREQUENTLY MUTATED GENES
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Schmidt, J., primary, Ramis-Záldivar, J., additional, Nadeu, F., additional, Gonzalez-Farre, B., additional, Navarro, A., additional, Dojcinov, S., additional, Rosenwald, A., additional, Ott, G., additional, Campo, E., additional, Fend, F., additional, Egan, C., additional, Jaffe, E., additional, Salaverria, I., additional, and Quintanilla-Martinez, L., additional
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- 2017
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28. GENE MUTATIONS AND COPY NUMBER ALTERATIONS (CNA) PREDICT FOR EARLY FAILURE IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) TREATED WITH R-CHOP
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Dlouhy, I., primary, Karube, K., additional, Enjuanes, A., additional, Salaverría, I., additional, Pérez-Galán, P., additional, Jares, P., additional, Martín-García, D., additional, Nadeu, F., additional, Rivas-Delgado, A., additional, Rovira, J., additional, Gonzalez, B., additional, Mozos, A., additional, Clot, G., additional, Sancho, J.M., additional, Salar, A., additional, Mercadal, S., additional, Escola, L., additional, Briones, J., additional, Colomo, L., additional, Alcoceba, M., additional, Valera, A., additional, Campo, E., additional, and López-Guillermo, A., additional
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- 2017
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29. SAT-149 - Polyploidy and chromosomal instability correlates with proliferative traits and lack of immune-related gene signatures in hepatocellular carcinoma
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Bassaganyas, L., Torrecilla, S., Moeini, A., Nadeu, F., Sia, D., Salaverria, I., Cabellos, L., Pinyol, R., Camps, J., Mazzaferro, V., and Llovet, J.M.
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- 2018
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30. Clinical impact of the subclonal architecture and mutational complexity in chronic lymphocytic leukemia
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Nadeu, F, Clot, G, Delgado, J, Martín-García, D, Baumann, T, Salaverria, I, Beà, S, Pinyol, M, Jares, P, Navarro, A, Suárez-Cisneros, H, Aymerich, M, Rozman, M, Villamor, N, Colomer, D, González, M, Alcoceba, M, Terol, M J, Navarro, B, Colado, E, Payer, ÁR, Puente, X S, López-Otín, C, López-Guillermo, A, Enjuanes, A, and Campo, E
- Abstract
Genome studies of chronic lymphocytic leukemia (CLL) have revealed the remarkable subclonal heterogeneity of the tumors, but the clinical implications of this phenomenon are not well known. We assessed the mutational status of 28 CLL driver genes by deep-targeted next-generation sequencing and copy number alterations (CNA) in 406 previously untreated patients and 48 sequential samples. We detected small subclonal mutations (0.6–25% of cells) in nearly all genes (26/28), and they were the sole alteration in 22% of the mutated cases. CNA tended to be acquired early in the evolution of the disease and remained stable, whereas the mutational heterogeneity increased in a subset of tumors. The prognostic impact of different genes was related to the size of the mutated clone. Combining mutations and CNA, we observed that the accumulation of driver alterations (mutational complexity) gradually shortened the time to first treatment independently of the clonal architecture, IGHV status and Binet stage. Conversely, the overall survival was associated with the increasing subclonal diversity of the tumors but it was related to the age of patients, IGHV and TP53 status of the tumors. In conclusion, our study reveals that both the mutational complexity and subclonal diversity influence the evolution of CLL.
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- 2018
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31. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets
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Karube, K, Enjuanes, A, Dlouhy, I, Jares, P, Martin-Garcia, D, Nadeu, F, Ordóñez, G R, Rovira, J, Clot, G, Royo, C, Navarro, A, Gonzalez-Farre, B, Vaghefi, A, Castellano, G, Rubio-Perez, C, Tamborero, D, Briones, J, Salar, A, Sancho, J M, Mercadal, S, Gonzalez-Barca, E, Escoda, L, Miyoshi, H, Ohshima, K, Miyawaki, K, Kato, K, Akashi, K, Mozos, A, Colomo, L, Alcoceba, M, Valera, A, Carrió, A, Costa, D, Lopez-Bigas, N, Schmitz, R, Staudt, L M, Salaverria, I, López-Guillermo, A, and Campo, E
- Abstract
Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.
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- 2018
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32. SOX11 expression is restricted to EBV-negative Burkitt lymphoma and is associated with molecular genetic features.
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Sureda-Gómez M, Iaccarino I, De Bolòs A, Meyer M, Balsas P, Richter J, Rodríguez ML, López C, Carreras-Caballé M, Glaser S, Nadeu F, Jares P, Clot G, Siciliano MC, Bellan C, Tornambè S, Boccacci R, Leoncini L, Campo E, Siebert R, Amador V, and Klapper W
- Subjects
- Humans, Gene Expression Regulation, Neoplastic, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Mutation, DNA Helicases genetics, DNA Helicases metabolism, Translocation, Genetic, Transcription Factors genetics, Transcription Factors metabolism, Male, Inhibitor of Differentiation Proteins genetics, Inhibitor of Differentiation Proteins metabolism, Nuclear Proteins, Burkitt Lymphoma genetics, Burkitt Lymphoma virology, Burkitt Lymphoma metabolism, Burkitt Lymphoma pathology, SOXC Transcription Factors genetics, SOXC Transcription Factors metabolism, Herpesvirus 4, Human genetics
- Abstract
Abstract: SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observed that the presence of Epstein-Barr virus (EBV) and SOX11 expression were mutually exclusive in BL. SOX11 expression in EBV-negative (EVB-) BL was associated with an IG∷MYC translocation generated by aberrant class switch recombination, whereas in EBV-negative (EBV-)/SOX11-negative (SOX11-) tumors the IG∷MYC translocation was mediated by mistaken somatic hypermutations. Interestingly, EBV- SOX11-expressing BL showed higher frequency of SMARCA4 and ID3 mutations than EBV-/SOX11- cases. By RNA sequencing, we identified a SOX11-associated gene expression profile, with functional annotations showing partial overlap with the SOX11 transcriptional program of MCL. Contrary to MCL, no differences on cell migration or B-cell receptor signaling were found between SOX11- and SOX11-positive (SOX11+) BL cells. However, SOX11+ BL showed higher adhesion to vascular cell adhesion molecule 1 (VCAM-1) than SOX11- BL cell lines. Here, we demonstrate that EBV- BL comprises 2 subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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33. Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target.
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Dobaño-López C, Valero JG, Araujo-Ayala F, Nadeu F, Gava F, Faria C, Norlund M, Morin R, Bernes-Lasserre P, Arenas F, Grau M, López C, López-Oreja I, Serrat N, Martínez-Farran A, Hernández L, Playa-Albinyana H, Giménez R, Beà S, Campo E, Lagarde JM, López-Guillermo A, Magnano L, Colomer D, Bezombes C, and Pérez-Galán P
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- Humans, Spheroids, Cellular, Immunotherapy methods, Signal Transduction, Tumor Cells, Cultured, Lymphoma, Follicular immunology, Lymphoma, Follicular pathology, Lymphoma, Follicular therapy, Galectins, Lymph Nodes pathology, Lymph Nodes immunology, Tumor Microenvironment immunology
- Abstract
Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches., (© 2024. The Author(s).)
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- 2024
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34. Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation.
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Playa-Albinyana H, Arenas F, Royo R, Giró A, López-Oreja I, Aymerich M, López-Guerra M, Frigola G, Beà S, Delgado J, Garcia-Roves PM, Campo E, Nadeu F, and Colomer D
- Subjects
- Humans, Animals, Mice, Heterografts, Clonal Evolution genetics, Prognosis, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5-10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT. Whole-genome sequencing analysis at different time points of the PDX evolution revealed a genomic landscape similar to RT tumors from both patients and uncovered an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. In PDX12, the transformed cells expanded from a very small subclone already present at the CLL stage. Transcriptomic analysis of PDXs showed a high oxidative phosphorylation (OXPHOS) and low B-cell receptor (BCR) signaling similar to the RT in the patients. IACS-010759, an OXPHOS inhibitor, reduced proliferation, and circumvented resistance to venetoclax. In summary, we have generated new RT-PDX models, one of them from CLL cells that mimicked the evolution of CLL to RT uncovering intrinsic features of RT cells of therapeutical value., (© 2023. The Author(s).)
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- 2024
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35. BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases.
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Carbo-Meix A, Guijarro F, Wang L, Grau M, Royo R, Frigola G, Playa-Albinyana H, Buhler MM, Clot G, Duran-Ferrer M, Lu J, Granada I, Baptista MJ, Navarro JT, Espinet B, Puiggros A, Tapia G, Bandiera L, De Canal G, Bonoldi E, Climent F, Ribera-Cortada I, Fernandez-Caballero M, De la Banda E, Do Nascimento J, Pineda A, Vela D, Rozman M, Aymerich M, Syrykh C, Brousset P, Perera M, Yanez L, Ortin JX, Tuset E, Zenz T, Cook JR, Swerdlow SH, Martin-Subero JI, Colomer D, Matutes E, Bea S, Costa D, Nadeu F, and Campo E
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Translocation, Genetic, Gene Rearrangement, Immunoglobulin Heavy Chains genetics, Chromosomes, Human, Pair 14 genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.
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- 2024
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36. Robust identification of conventional and leukemic nonnodal mantle cell lymphomas using epigenetic biomarkers.
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Bühler MM, Kulis M, Duran-Ferrer M, López C, Clot G, Nadeu F, Romo M, Giné E, López-Guillermo A, Beà S, Campo E, and Martín-Subero JI
- Abstract
Competing Interests: The authors declare no conflict of interest.
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- 2024
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37. A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.
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Mozas P, Casanueva-Eliceiry S, Rivero A, Serna Á, Simó M, Rodríguez S, Rivas-Delgado A, Nadeu F, Correa JG, Piñeyroa JA, Pérez-Valencia AI, Guinetti-Ortiz K, Gómez-Hernando M, Giné E, Delgado J, Villamor N, Campo E, Magnano L, Abrisqueta P, Setoain X, and López-Guillermo A
- Subjects
- Humans, Tumor Burden, Prognosis, Fluorodeoxyglucose F18, Proportional Hazards Models, Positron Emission Tomography Computed Tomography methods, Retrospective Studies, Lymphoma, Follicular therapy
- Abstract
Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)
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- 2024
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38. IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia.
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Syrykh C, Pons-Brun B, Russiñol N, Playa-Albinyana H, Baumann T, Duran-Ferrer M, Kulis M, Carbó-Meix A, Mozas P, Alcoceba M, González M, Navarro-Bailón A, Colado E, Payer ÁR, Aymerich M, Terol MJ, Lu J, Knisbacher BA, Hahn CK, Ruiz-Gaspà S, Enjuanes A, Wu CJ, Getz G, Zenz T, López-Guillermo A, Martín-Subero JI, Colomer D, Delgado J, Campo E, and Nadeu F
- Subjects
- Humans, Prognosis, Mutation, Immunoglobulin Heavy Chains genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Published
- 2023
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39. From genetics to therapy: Unraveling the complexities of Richter transformation in chronic lymphocytic leukemia.
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Abrisqueta P, Nadeu F, Bosch-Schips J, Iacoboni G, Serna A, Cabirta A, Yáñez L, Quintanilla-Martínez L, and Bosch F
- Abstract
Richter transformation (RT) refers to the progression of chronic lymphocytic leukemia, the most prevalent leukemia among adults, into a highly aggressive lymphoproliferative disorder, primarily a diffuse large B-cell lymphoma. This is a severe complication that continues to be a therapeutic challenge and remains an unmet medical need. Over the last five years, significant advances have occurred in uncovering the biological processes leading to the RT, refining criteria for properly diagnose RT from other entities, and exploring new therapeutic options beyond the ineffective chemotherapy. This review summarizes current knowledge in RT, including recent advances in the understanding of the pathogenesis of RT, in the classification of RT, and in the development of novel therapeutic strategies for this grave complication., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)
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- 2023
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40. MALAT1 expression is associated with aggressive behavior in indolent B-cell neoplasms.
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Fernández-Garnacho EM, Nadeu F, Martín S, Mozas P, Rivero A, Delgado J, Giné E, López-Guillermo A, Duran-Ferrer M, Salaverria I, López C, Beà S, Demajo S, Jares P, Puente XS, Martín-Subero JI, Campo E, and Hernández L
- Subjects
- Humans, Genes, Neoplasm, Prognosis, Tumor Microenvironment genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Follicular genetics, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients., (© 2023. Springer Nature Limited.)
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- 2023
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41. Genomic landscape of follicular lymphoma across a wide spectrum of clinical behaviors.
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Mozas P, López C, Grau M, Nadeu F, Clot G, Valle S, Kulis M, Navarro A, Ramis-Zaldivar JE, González-Farré B, Rivas-Delgado A, Rivero A, Frigola G, Balagué O, Giné E, Delgado J, Villamor N, Matutes E, Magnano L, García-Sanz R, Huet S, Russell RB, Campo E, López-Guillermo A, and Beà S
- Subjects
- Humans, Neoplasm Recurrence, Local, Mutation, Genomics, Recurrence, Lymphoma, Follicular pathology
- Abstract
While some follicular lymphoma (FL) patients do not require treatment or experience prolonged responses, others relapse early, and little is known about genetic alterations specific to patients with a particular clinical behavior. We selected 56 grade 1-3A FL patients according to their need of treatment or timing of relapse: never treated (n = 7), non-relapsed (19), late relapse (14), early relapse or POD24 (11), and primary refractory (5). We analyzed 56 diagnostic and 12 paired relapse lymphoid tissue biopsies and performed copy number alteration (CNA) analysis and next generation sequencing (NGS). We identified six focal driver losses (1p36.32, 6p21.32, 6q14.1, 6q23.3, 9p21.3, 10q23.33) and 1p36.33 copy-neutral loss of heterozygosity (CN-LOH). By integrating CNA and NGS results, the most frequently altered genes/regions were KMT2D (79%), CREBBP (67%), TNFRSF14 (46%) and BCL2 (40%). Although we found that mutations in PIM1, FOXO1 and TMEM30A were associated with an adverse clinical behavior, definitive conclusions cannot be drawn, due to the small sample size. We identified common precursor cells harboring early oncogenic alterations of the KMT2D, CREBBP, TNFRSF14 and EP300 genes and 16p13.3-p13.2 CN-LOH. Finally, we established the functional consequences of mutations by means of protein modeling (CD79B, PLCG2, PIM1, MCL1 and IRF8). These data expand the knowledge on the genomics behind the heterogeneous FL population and, upon replication in larger cohorts, could contribute to risk stratification and the development of targeted therapies., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)
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- 2023
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42. All-CLL: A Capture-based Next-generation Sequencing Panel for the Molecular Characterization of Chronic Lymphocytic Leukemia.
- Author
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López-Oreja I, López-Guerra M, Correa J, Mozas P, Muntañola A, Muñoz L, Salgado AC, Ruiz-Gaspà S, Costa D, Beà S, Jares P, Campo E, Colomer D, and Nadeu F
- Abstract
Competing Interests: EC has been a consultant for Takeda, NanoString, AbbVie, and Illumina; has received honoraria from Janssen, EUSPharma, and Roche for speaking at educational activities and research funding from AstraZeneca and is an inventor on 2 patents filed by the National Institutes of Health, National Cancer Institute: “Methods for selecting and treating lymphoma types,” licensed to NanoString Technologies, and “Evaluation of mantle cell lymphoma and methods related thereof,” not related to this project. DC has received honoraria from AbbVie and AstraZeneca for speaking at educational activities. FN has received honoraria from Janssen, AbbVie, and SOPHiA GENETICS for speaking at educational activities. FN and EC have licensed the use of the protected IgCaller algorithm to Diagnóstica Longwood. All the other authors have no conflicts of interest to disclose.
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- 2023
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43. MYC and TP53 Alterations but Not MAPK Pathway Mutations Are Common Oncogenic Mechanisms in Follicular Dendritic Cell Sarcomas.
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Frigola G, Bühler M, Marginet M, Enjuanes A, Nadeu F, Papaleo N, Salido M, Haralambieva E, Alamo J, Garcia-Bragado F, Álvarez R, Ramos R, Aldecoa I, Campo E, Colomo L, and Balagué O
- Subjects
- Humans, Carcinogenesis genetics, Herpesvirus 4, Human genetics, Mutation, Tumor Suppressor Protein p53 genetics, Dendritic Cell Sarcoma, Follicular genetics, Dendritic Cell Sarcoma, Follicular pathology, Epstein-Barr Virus Infections, Sarcoma
- 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., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2023 College of American Pathologists.)
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- 2023
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44. Unraveling the genetics of transformed splenic marginal zone lymphoma.
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Grau M, López C, Navarro A, Frigola G, Nadeu F, Clot G, Bastidas-Mora G, Alcoceba M, Baptista MJ, Blanes M, Colomer D, Costa D, Domingo-Domènech E, Enjuanes A, Escoda L, Forcada P, Giné E, Lopez-Guerra M, Ramón O, Rivas-Delgado A, Vicente Folch L, Wotherspoon A, Climent F, Campo E, López-Guillermo A, Matutes E, and Beà S
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- Humans, Mutation, Translocation, Genetic, Splenic Neoplasms genetics, Splenic Neoplasms diagnosis, Splenic Neoplasms pathology, Lymphoma, Large B-Cell, Diffuse genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
The genetic mechanisms associated with splenic marginal zone lymphoma (SMZL) transformation are not well defined. We studied 41 patients with SMZL that eventually underwent large B-cell lymphoma transformation. Tumor material was obtained either only at diagnosis (9 patients), at diagnosis and transformation (18 patients), and only at transformation (14 patients). Samples were categorized in 2 groups: (1) at diagnosis (SMZL, n = 27 samples), and (2) at transformation (SMZL-T, n = 32 samples). Using copy number arrays and a next-generation sequencing custom panel, we identified that the main genomic alterations in SMZL-T involved TNFAIP3, KMT2D, TP53, ARID1A, KLF2, 1q gains, and losses of 9p21.3 (CDKN2A/B) and 7q31-q32. Compared with SMZL, SMZL-T had higher genomic complexity, and higher incidence of TNFAIP3 and TP53 alterations, 9p21.3 (CDKN2A/B) losses, and 6p gains. SMZL and SMZL-T clones arose by divergent evolution from a common altered precursor cell that acquired different genetic alterations in virtually all evaluable cases (92%, 12 of 13 cases). Using whole-genome sequencing of diagnostic and transformation samples in 1 patient, we observed that the SMZL-T sample carried more genomic aberrations than the diagnostic sample, identified a translocation t(14;19)(q32;q13) present in both samples, and detected a focal B2M deletion due to chromothripsis acquired at transformation. Survival analysis showed that KLF2 mutations, complex karyotype, and International Prognostic Index score at transformation were predictive of a shorter survival from transformation (P = .001; P = .042; and P = .007; respectively). In summary, SMZL-T are characterized by higher genomic complexity than SMZL, and characteristic genomic alterations that could represent key players in the transformation event., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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45. Chromatin activation profiling of stereotyped chronic lymphocytic leukemias reveals a subset 8-specific signature.
- Author
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Tsagiopoulou M, Chapaprieta V, Russiñol N, García-Torre B, Pechlivanis N, Nadeu F, Papakonstantinou N, Stavroyianni N, Chatzidimitriou A, Psomopoulos F, Campo E, Stamatopoulos K, and Martín-Subero JI
- Subjects
- Humans, Chromatin genetics, B-Lymphocytes, Receptors, Antigen, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse
- Abstract
The chromatin activation landscape of chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor immunoglobulin is currently unknown. In this study, we report the results of a whole-genome chromatin profiling of histone 3 lysine 27 acetylation of 22 CLLs from major subsets, which were compared against nonstereotyped CLLs and normal B-cell subpopulations. Although subsets 1, 2, and 4 did not differ much from their nonstereotyped CLL counterparts, subset 8 displayed a remarkably distinct chromatin activation profile. In particular, we identified 209 de novo active regulatory elements in this subset, which showed similar patterns with U-CLLs undergoing Richter transformation. These regions were enriched for binding sites of 9 overexpressed transcription factors. In 78 of 209 regions, we identified 113 candidate overexpressed target genes, 11 regions being associated with more than 2 adjacent genes. These included blocks of up to 7 genes, suggesting local coupregulation within the same genome compartment. Our findings further underscore the uniqueness of subset 8 CLL, notable for the highest risk of Richter's transformation among all CLLs and provide additional clues to decipher the molecular basis of its clinical behavior., (© 2023 by The American Society of Hematology.)
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- 2023
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46. A novel patient-derived 3D model recapitulates mantle cell lymphoma lymph node signaling, immune profile and in vivo ibrutinib responses.
- Author
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Araujo-Ayala F, Dobaño-López C, Valero JG, Nadeu F, Gava F, Faria C, Norlund M, Morin R, Bernes-Lasserre P, Serrat N, Playa-Albinyana H, Giménez R, Campo E, Lagarde JM, López-Guillermo A, Gine E, Colomer D, Bezombes C, and Pérez-Galán P
- Subjects
- Humans, Adult, Cell Line, Tumor, Drug Resistance, Neoplasm, Adenine therapeutic use, Tumor Microenvironment, Lymphoma, Mantle-Cell pathology
- Abstract
Mantle cell lymphoma (MCL), a rare and aggressive B-cell non-Hodgkin lymphoma, mainly develops in the lymph node (LN) and creates a protective and immunosuppressive niche that facilitates tumor survival, proliferation and chemoresistance. To capture disease heterogeneity and tumor microenvironment (TME) cues, we have developed the first patient-derived MCL spheroids (MCL-PDLS) that recapitulate tumor oncogenic pathways and immune microenvironment in a multiplexed system that allows easy drug screening, including immunotherapies. MCL spheroids, integrated by tumor B cells, monocytes and autologous T-cells self-organize in disc-shaped structures, where B and T-cells maintain viability and proliferate, and monocytes differentiate into M2-like macrophages. RNA-seq analysis demonstrated that tumor cells recapitulate hallmarks of MCL-LN (proliferation, NF-kB and BCR), with T cells exhibiting an exhaustion profile (PD1, TIM-3 and TIGIT). MCL-PDLS reproduces in vivo responses to ibrutinib and demonstrates that combination of ibrutinib with nivolumab (anti-PD1) may be effective in ibrutinib-resistant cases by engaging an immune response with increased interferon gamma and granzyme B release. In conclusion, MCL-PDLS recapitulates specific MCL-LN features and in vivo responses to ibrutinib, representing a robust tool to study MCL interaction with the immune TME and to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches., (© 2023. The Author(s).)
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- 2023
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47. RFcaller: a machine learning approach combined with read-level features to detect somatic mutations.
- Author
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Díaz-Navarro A, Bousquets-Muñoz P, Nadeu F, López-Tamargo S, Beà S, Campo E, and Puente XS
- Abstract
The cost reduction in sequencing and the extensive genomic characterization of a wide variety of cancers are expanding tumor sequencing to a wide number of research groups and the clinical practice. Although specific pipelines have been generated for the identification of somatic mutations, their results usually differ considerably, and a common approach is to use several callers to achieve a more reliable set of mutations. This procedure is computationally expensive and time-consuming, and it suffers from the same limitations in sensitivity and specificity as other approaches. Expert revision of mutant calls is therefore required to verify calls that might be used for clinical diagnosis. This step could take advantage of machine learning techniques, as they provide a useful approach to incorporate expert-reviewed information for the identification of somatic mutations. Here we present RFcaller, a pipeline based on machine learning algorithms, for the detection of somatic mutations in tumor-normal paired samples that does not require large computing resources. RFcaller shows high accuracy for the detection of substitutions and insertions/deletions from whole genome or exome data. It allows the detection of mutations in driver genes missed by other approaches, and has been validated by comparison to deep and Sanger sequencing., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)
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- 2023
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48. Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma.
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Sureda-Gómez M, Balsas P, Rodríguez ML, Nadeu F, De Bolòs A, Eguileor Á, Kulis M, Castellano G, López C, Giné E, Demajo S, Jares P, Martín-Subero JI, Beà S, Campo E, and Amador V
- Subjects
- Animals, Mice, SOXC Transcription Factors genetics, Lymphoma, Mantle-Cell pathology, RNA-Binding Proteins metabolism
- Abstract
SOX11 overexpression has been associated with aggressive behavior of mantle cell lymphomas (MCL). SOX11 is overexpressed in embryonic and cancer stem cells (CSC) of some tumors. Although CSC have been isolated from primary MCL, their relationship to SOX11 expression and contribution to MCL pathogenesis and clinical evolution remain unknown. Here, we observed enrichment in leukemic and hematopoietic stem cells gene signatures in SOX11+ compared to SOX11- MCL primary cases. Musashi-2 (MSI2) emerged as one of the most significant upregulated stem cell-related genes in SOX11+ MCLs. SOX11 is directly bound to the MSI2 promoter upregulating its expression in vitro. MSI2 intronic enhancers were strongly activated in SOX11+ MCL cell lines and primary cases. MSI2 upregulation was significantly associated with poor overall survival independently of other high-risk features of MCL. MSI2 knockdown decreased the expression of genes related to apoptosis and stem cell features and significantly reduced clonogenic growth, tumor cell survival and chemoresistance in MCL cells. MSI2-knockdown cells had reduced tumorigenic engraftment into mice bone marrow and spleen compared to control cells in xenotransplanted mouse models. Our results suggest that MSI2 might play a key role in sustaining stemness and tumor cell survival, representing a possible novel target for therapeutic interventions in MCL., (© 2022. The Author(s).)
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- 2023
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49. Correction: Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
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Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, and Rosenquist R
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- 2023
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50. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
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Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, and Rosenquist R
- Subjects
- Humans, Prognosis, Myeloid Differentiation Factor 88 genetics, Mutation, Phenotype, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management., (© 2022. The Author(s).)
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- 2023
- Full Text
- View/download PDF
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