Author:
Carbo-Meix Anna,Guijarro Francesca,Wang Luojun,Grau Marta,Royo Romina,Frigola Gerard,Playa-Albinyana Heribert,Buhler Marco M.,Clot Guillem,Duran-Ferrer Marti,Lu Junyan,Granada Isabel,Baptista Maria-Joao,Navarro Jose-Tomas,Espinet Blanca,Puiggros Anna,Tapia Gustavo,Bandiera Laura,De Canal Gabriella,Bonoldi Emanuela,Climent Fina,Ribera-Cortada Inmaculada,Fernandez-Caballero Mariana,De la Banda Esmeralda,Do Nascimento Janilson,Pineda Alberto,Vela Dolors,Rozman Maria,Aymerich Marta,Syrykh Charlotte,Brousset Pierre,Perera Miguel,Yanez Lucrecia,Ortin Jesus Xavier,Tuset Esperanza,Zenz Thorsten,Cook James R.,Swerdlow Steven H.,Martin-Subero Jose I.,Colomer Dolors,Matutes Estella,Bea Silvia,Costa Dolors,Nadeu Ferran,Campo Elias
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.
Publisher
Ferrata Storti Foundation (Haematologica)