Mutational profile dynamics in follicular lymphoma and large cell transformation.

Aims: Follicular lymphoma (FL) is characterised by significant heterogeneity in both the clinical trajectories and the molecular profiles. This study aimed to investigate clonal dynamics in FL by analysing mutation profiles at various time points during the disease course including at histological transformation (HT), to gain insight into the mutational changes over time.

Methods: We retrospectively analysed 76 biopsies from 25 patients, including 13 cases with three or more FL biopsies and 12 cases with subsequent HT. Hybrid capture-based Next-Generation Sequencing (NGS) with the EuroClonality-NGS DNA capture (EuroClonality-NDC) assay was used to examine clonal rearrangements and mutations.

Results: A total of 204 (potentially) pathogenic mutations were identified. Only 40% of mutations remained stably present during a median follow-up period of 139 months (range 9-198). KMT2D and CREBBP were the most frequently mutated genes at diagnosis, exhibiting relative stability in follow-up biopsies. Conversely, EZH2 displayed a dynamic pattern of mutations gained and lost during the disease course. At HT, pathogenic mutations affecting B2M, MYC and TP53 emerged. Changes in mutational burden were observed in both FL-sequential and diagnosis-transformation cohorts, with more pronounced changes in the latter.

Conclusions: This real-world study provides insights into the complex molecular pathogenesis of FL and HT. As targeted therapies emerge as treatment modalities, mutational profiles could influence treatment decisions in the future. Therefore, recognising the significant changes occurring in the mutational landscape of FL throughout the disease course is crucial.