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This work was supported by Asociacion Espanola Contra el Cancer (AECC CICPFI6025SALA), Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III (Miguel Servet Program CP13/00159 and PI15/00580 to I.S.), Spanish Ministerio de Economia y Competitividad (SAF201564885-R to E.C.), Generalitat de Catalunya Suport Grups de Recerca (2017-SGR-1107 to I.S. and 2017-SGR-1142 to E.C.), SPECS II grant (National Cancer Institute 1U01CA157581), and the European Regional Development Fund (Una manera de fer Europa). J.E.R.-Z. was supported by a fellowship from Generalitat de Catalunya AGAUR FI-DGR 2017 (2017 FI_B01004). E.C. is an Academia Researcher of the Institucio ' Catalana de Recerca i Estudis Avancats of the Generalitat de Catalunya. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain. The group is supported by Accioinstrumental d'incorporacio de cientifics i tecnolegs PERIS 2016 (SLT002/16/00336 to Noelia Garcia) from Generalitat de Catalunya.

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Distinct molecular profile of IRF4-rearranged large B-cell lymphoma

Publicado en:Blood. 135 (4): 274-286 - 2020-01-23 135(4), DOI: 10.1182/blood.2019002699

Autores: Enric Ramis-Zaldivar, Joan; Gonzalez-Farre, Blanca; Balague, Olga; Celis, Veronica; Nadeu, Ferran; Salmeron-Villalobos, Julia; Andres, Mara; Martin-Guerrero, Idoia; Garrido-Pontnou, Marta; Gaafar, Ayman; Sunol, Mariona; Barcena, Carmen; Garcia-Bragado, Federico; Andion, Maitane; Azorin, Daniel; Astigarraga, Itziar; Sagaseta de Ilurdoz, Maria; Sabado, Constantino; Gallego, Soledad; Verdu-Amoros, Jaime; Fernandez-Delgado, Rafael; Perez, Vanesa; Tapia, Gustavo; Mozos, Anna; Torrent, Montserrat; Solano-Paez, Palma; Rivas-Delgado, Alfredo; Dlouhy, Ivan; Clot, Guillem; Enjuanes, Anna; Lopez-Guillermo, Armando; Galera, Pallavi; Oberley, Matthew J; Maguire, Alanna; Ramsower, Colleen; Rimsza, Lisa M; Quintanilla-Martinez, Leticia; Jaffe, Elaine S; Campo, Elias; Salaverria, Itziar

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Resumen

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.Copyright © 2019 American Society of Hematology.

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