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This work was supported, in part, by grants from the Deutsche Forschungsgemeinschaft (DFG; QU144/1-1 [L.Q.-M.], FE597/4-1 [F.F.], and QU144/1-1 [I.M.]), Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III (Miguel Servet Program CP13/00159 and PI15/00580, [I.S.]). J.E.R.-Z. was supported by a fellowship from theGeneralitat deCatalunyaAgencia de Gestion de la Universidad la Investigacion (AGAUR) FI-DGR 2017 (2017 FI_B01004). E.C. is an Academia Researcher of the Institucio Catalana de Recerca I Estudis Avancats (ICREA) of the Generalitat de Catalunya. This work was partially developed at the Centro Esther Koplowitz, Barcelona, Spain. I.S. is supported by Accio Instrumental d'Incorporacio de Cientifics i Tecnolegs Plan de Investigacion e Innovacion en Salud (PERIS) 2016 (SLT002/16/00336) from the Generalitat de Catalunya.

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Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease

Publicat a:Blood Advances. 4 (22): 5652-5665 - 2020-11-24 4(22), DOI: 10.1182/bloodadvances.2020002944

Autors: Nann, Dominik; Ramis-Zaldivar, Joan Enric; Muller, Inga; Gonzalez-Farre, Blanca; Schmidt, Janine; Egan, Caoimhe; Salmeron-Villalobos, Julia; Clot, Guillem; Mattern, Sven; Otto, Franziska; Mankel, Barbara; Colomer, Dolors; Balague, Olga; Szablewski, Vanessa; Lome-Maldonado, Carmen; Leoncini, Lorenzo; Dojcinov, Stefan; Chott, Andreas; Copie-Bergman, Christiane; Bonzheim, Irina; Fend, Falko; Jaffe, Elaine S; Campo, Elias; Salaverria, Itziar; Quintanilla-Martinez, Leticia

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Fifty-five cases of t(14;18)- follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)- FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)- FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)- FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)- FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

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