Hesius Eva A M, Stevens Wendy B C, Stewart James P, Kroeze Leonie I, Spek Ellen van der, Issa Djamila, Nooijen Peet, Luijks Jeroen, Gonzalez David, Groenen Patricia J T A, Blijlevens Nicole M A, Spriel Annemiek B van, Brand Michiel van den
Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands
Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands.
J Clin Pathol. 2025 Jun 19;78(7):473-482. doi: 10.1136/jcp-2024-209880.
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.
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.
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). and were the most frequently mutated genes at diagnosis, exhibiting relative stability in follow-up biopsies. Conversely, displayed a dynamic pattern of mutations gained and lost during the disease course. At HT, pathogenic mutations affecting , and emerged. Changes in mutational burden were observed in both FL-sequential and diagnosis-transformation cohorts, with more pronounced changes in the latter.
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.
滤泡性淋巴瘤（FL）在临床病程和分子特征方面均具有显著的异质性。本研究旨在通过分析疾病过程中各个时间点（包括组织学转化时）的突变谱来研究FL中的克隆动态，以深入了解随时间的突变变化。
我们回顾性分析了25例患者的76份活检样本，其中13例有三次或更多次FL活检样本，12例有后续的组织学转化。采用基于杂交捕获的新一代测序（NGS）和EuroClonality-NGS DNA捕获（EuroClonality-NDC）检测法来检测克隆重排和突变。
共鉴定出204个（潜在）致病突变。在139个月（范围9 - 198个月）的中位随访期内，只有40%的突变稳定存在。 和 是诊断时最常发生突变的基因，在随访活检中表现出相对稳定性。相反， 在疾病过程中呈现出获得和丢失突变的动态模式。在组织学转化时，影响 、 和 的致病突变出现。在FL连续活检队列和诊断 - 转化队列中均观察到突变负担的变化，后者的变化更为明显。
这项真实世界研究为FL和组织学转化的复杂分子发病机制提供了见解。随着靶向治疗成为治疗方式，突变谱可能会影响未来的治疗决策。因此，认识到FL在整个疾病过程中突变格局发生的显著变化至关重要。
