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Vol. 24, Art. 84 (pp. 1223-1236)    |    2023       

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EZH2 is a new target target in follicular lymphoma: Literature review and own data

Kunevich E.O.1, Voloshin S.V.1,2, Martynkevich I.S.1, Motyko E.V.1, Baram D.V.1, Kuvshinov A.Y.1, Sidorkevich S.V.1

1Russian Research Institute of Hematology and Transfusiology, Saint-Petersburg, Russia
2Military Medical Academy named after S.M. Kirov, Saint-Petersburg, Russia,
For correspondence: Kunevich Evgenii Olegovich, E-mail: kunevich17@gmail.ru

Brief summary

Introduction. The key cytogenetic marker of follicular lymphoma (FL) is the reciprocal translocation t(14;18)(q32.3;q21.3), detected in 80-85% of patients. However, the development of FL requires additional genetic events, including mutations in the EZH2 gene. Changing the paradigm of therapeutic approaches in FL, the inclusion of new targeted drugs in treatment programs for relapsed and refractory forms of the disease suggests the identification of new predictors of the effectiveness of therapy, such as the mutational status of the EZH2 gene. A recently developed oral selective inhibitor of EZH2 (tazemetostat) has demonstrated high efficacy in the treatment of relapsed and refractory FL. Aim. To determine the frequency of occurrence of mutations in the EZH2 gene in patients with FL using Sanger sequencing and next generation sequencing (NGS). Materials and methods. The study included 111 patients over 18 years of age with newly confirmed follicular lymphoma. The mutational status of exon 16 of the EZH2 gene was assessed using Sanger sequencing (n = 111). NGS analysis was performed on the NextSeq platform (Illumina, USA) by paired-end reading using a panel of probes for 118 genes in 25 patients. Rearrangements of the BCL2, BCL6, and del17p/TP53 genes were determined by fluorescent in situ hybridization (FISH), which were evaluated in 105 patients. The obtained data were analyzed using IBM SPSS Statistics 26, R version 4.2.2 software. Results. The frequency of mutations according to the results of Sanger sequencing was 17%, according to NGS - 12%. All patients had a missense mutation of the tyrosine amino acid substitution at position 646 (p.Y646X). According to the results of NGS, the highest mutation frequency was noted in the genes: KMT2C - 52%, KMT2D - 48%, CREBBP - 32%, NOTCH2 - 32%, GNAS - 24%, FAT1, ITPKB and KDR - 20% each. EZH2 gene mutations were associated with cytological type 1-2, as well as with mutations in the CREBBP (p = 0.004), KMT2D (p = 0.032), and KDR (p = 0.026) genes. Conclusions. The mutation rate of the EZH2 gene, estimated by NGS and Sanger sequencing, in the Russian cohort of patients is 12-17%, which is consistent with the data of international studies. Taking into account the relatively high frequency of occurrence, as well as the accumulated data on the pathogenetic role, mutations in the EZH2 gene are an important predictor and one of the main targets of therapeutic intervention in patients with FL.


Key words

follicular lymphoma, epigenetics, polycomb repressive complex 2 (PRC2), EZH2 gene mutations, H3K27 methylation, next generation sequencing (NGS), tazemetostat, targeted therapy.

Reference list

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