Molecular mechanisms of follicular lymphoma and its transformation

Abstract

Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma and at least a third of cases undergo aggressive transformation (t-FL), most frequently to diffuse large B-cell lymphoma. This study examined the role of germline and acquired genetic changes in FL and t-FL to determine prognostically significant events and chart the evolution of transformation. Assessment of germline polymorphic variation in over 200 FL cases demonstrated two SNPs in the HLA region of chromosome 6p (rs10484561 and rs6457327) associate with FL risk in the UK and identified that rs6457327 predicts both time to and risk of transformation independently of clinical variables, including the FLIPI. Mutation and expression studies of the single known gene in linkage disequilibrium with rs6457327 (C6orf15) suggest an alternative mechanism is responsible for this transformation association. DNA copy number and mutational analysis of FL and t-FL samples then revealed a high prevalence of TNFSRF14 and EZH2 mutations at transformation accompanied by frequent loss and gain of their genomic locations on chromosome 1p and 7q, respectively. In a search for co-operating genetic events, genome-wide profiling identified recurrent losses and gains ranging from 4 kb to 60 Mb with gain 2p16.1-p15 (including REL) predictive of worse survival in FL that transforms. In >50% of transformed cases, FL DNA contained either copy number aberrations or mutations that were absent from subsequent t-FL. This suggested FL and t-FL might develop non-sequentially from a common cell of origin. To further explore the evolution of FL and t-FL, IGH-V somatic-hypermutation (SHM) analysis was performed in sequential FL / t-FL samples. t-FL clones were detected in FL samples taken many months prior to clinical presentation of transformation and, furthermore, the predicted SHM patterns of putative precursors were detected in both FL and t-FL samples indicating that a (long-lived) common progenitor cell could indeed give rise to both FL and subsequent t-FL by divergent clonal evolution.