Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma
Lucía Pedrosa, Ismael Fernández‐Miranda, David Pérez-Callejo, Cristina Quero, Marta Rodríguez, Paloma Martín, Sagrario Gómez, Julia González‐Rincón, Adrián Santos, Carlos Tarín, Juan F. Garcı́a, Francisco R. García-Arroyo, Antonio Rueda, Francisca I. Camacho, Mónica García‐Cosío, Ana Heredero, Marta Llanos, Manuela Mollejo, Miguel Piris‐Villaespesa, José Gómez‐Codina, Natalia Yanguas‐Casás, Antonio Sánchez, Miguel Á. Piris, Mariano Provencio, Margarita Sánchez‐Beato
Abstract
Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B , ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N1 2-S , EZB 2-S , MCD 2-S , BN2 2-S , and ST2 2-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST2 2-S is the group with the best clinical outcome and N1 2-S , the more aggressive one. EZB 2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.