Date Published: February 25, 2019
Publisher: Public Library of Science
Author(s): Julia González-Rincón, Miriam Méndez, Sagrario Gómez, Juan F. García, Paloma Martín, Carmen Bellas, Lucía Pedrosa, Socorro M. Rodríguez-Pinilla, Francisca I. Camacho, Cristina Quero, David Pérez-Callejo, Antonio Rueda, Marta Llanos, José Gómez-Codina, Miguel A. Piris, Santiago Montes-Moreno, Carmen Bárcena, Delvys Rodríguez-Abreu, Javier Menárguez, Luis de la Cruz-Merino, Silvia Monsalvo, Consuelo Parejo, Ana Royuela, Ivo Kwee, Luciano Cascione, Alberto Arribas, Francesco Bertoni, Manuela Mollejo, Mariano Provencio, Margarita Sánchez-Beato, Javier Marcelo Di Noia.
Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.
Follicular lymphoma (FL) is an indolent, but typically incurable disease with a long natural history. FL patients respond to a variety of treatments and have a median overall survival (OS) of >10 years in the immunochemotherapy era , but the outcome is variable: some patients do not need treatment, while others follow a more aggressive course characterized by interspersed episodes of remission and relapse, associated with lower sensitivity to therapy [2,3]. The reported frequency of histological transformation (HT) into a more aggressive lymphoma (transformed FL or tFL), most commonly diffuse large B-cell lymphoma (DLBCL), varies markedly, from 30% to 60% of patients. HT has been associated with poor prognosis, and in more than half of cases, occurred within the first year of follow-up [3,4].
In this study, we analyzed paired samples from transformed FL and samples from non-transformed patients by targeted massive parallel sequencing and SNP arrays.