Parallel testing of liquid biopsy (ctDNA) and tissue biopsy samples reveals a higher frequency of EZH2 mutations in follicular lymphoma

Nagy, Ákos and Bátai, Bence and Kiss, Laura and Gróf, Stefánia and Király, Péter Attila and Jóna, Ádám and Demeter, Judit and Sánta, Hermina and Bátai, Árpád and Pettendi, Piroska and Szendrei, Tamás and Plander, Márk and Körösmezey, Gábor and Alizadeh, Hussain and Kajtár, Béla and Méhes, Gábor and Krenács, László and Timár, Botond and Csomor, Judit and Tóth, Erika and Schneider, Tamás and Mikala, Gábor and Matolcsy, András and Alpár, Donát and Masszi, András and Bödör, Csaba (2023) Parallel testing of liquid biopsy (ctDNA) and tissue biopsy samples reveals a higher frequency of EZH2 mutations in follicular lymphoma. JOURNAL OF INTERNAL MEDICINE, 294 (3). pp. 295-313. ISSN 0954-6820

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Abstract

Background Recent genomic studies revealed enhancer of zeste homolog 2 (EZH2) gain-of-function mutations, representing novel therapeutic targets in follicular lymphoma (FL) in around one quarter of patients. However, these analyses relied on single-site tissue biopsies and did not investigate the spatial heterogeneity and temporal dynamics of these alterations. Objectives We aimed to perform a systematic analysis of EZH2 mutations using paired tissue (tumor biopsies [TB]) and liquid biopsies (LB) collected prior to treatment within the framework of a nationwide multicentric study. Methods Pretreatment LB and TB samples were collected from 123 patients. Among these, 114 had paired TB and LB, with 39 patients characterized with paired diagnostic and relapse samples available. The EZH2 mutation status and allele burden were assessed using an in-house-designed, highly sensitive multiplex droplet digital PCR assay. Results EZH2 mutation frequency was found to be 41.5% in the entire cohort. In patients with paired TB and LB samples, EZH2 mutations were identified in 37.8% of the patients with mutations exclusively found in 5.3% and 7.9% of TB and LB samples, respectively. EZH2 mutation status switch was documented in 35.9% of the patients with paired diagnostic and relapse samples. We also found that EZH2 wild-type clones may infiltrate the bone marrow more frequently compared to the EZH2 mutant ones. Conclusion The in-depth spatio-temporal analysis identified EZH2 mutations in a considerably higher proportion of patients than previously reported. This expands the subset of FL patients who most likely would benefit from EZH2 inhibitor therapy.

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