Identification of Somatic Mutations in EZH2 Gene and Assessment of Their Prognostic Value in Follicular Lymphoma Grades 1–3А

AUTOIMMUNE THROMBOCYTOPENIA

ES Nesterova, NA Severina, BV Biderman, AB Sudarikov, AM Kovrigina, TN Obukhova, YaK Mangasarova, SM Kulikov, EE Zvonkov, EN Parovichnikova, VG Savchenko

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Ekaterina Sergeevna Nesterova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-23-61, +7(910)429-62-26; e-mail: nest.ek@yandex.ru

For citation: Nesterova ES, Severina NA, Biderman BV, et al. Identification of Somatic Mutations in EZH2 Gene and Assessment of Their Prognostic Value in Follicular Lymphoma Grades 1–3А. Clinical oncohematology. 2023;16(1):80–7. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-80-87

ABSTRACT

Aim. To determine the incidence and prognostic value of mutations in exon 16 of EZH2 as well as those of polymorphism с.1582-21А>G (rs2072407) in EZH2 in patients with follicular lymphoma (FL) grades 1–3А in relation to morphologic and cytogenetic tumor characteristics.

Materials & Methods. The prospective cohort study conducted by the National Research Center for Hematology from January 2017 to April 2021 enrolled 80 patients with newly diagnosed FL grades 1/2 and 3А. The median follow-up was 53 months. Molecular and cytogenetic analyses were based on biopsy samples of lymph nodes obtained before chemotherapy. The mutation status of exon 16 in EZH2 and the presence of intronic polymorphism rs2072407 in EZH2 were examined by Sanger sequencing method. Translocation t(14;18)(q32;q21) was detected by karyotyping or FISH.

Results. Mutations in exon 16 of EZH2 (mutEZH2) were identified in 10/80 (13 %) patients. All patients showed missense mutation in codon 646 of EZH2. Translocation t(14;18) was detected in 45/80 (56 %) cases. Poor outcome in the cohort with no t(14;18) was observed 3 times more often than in the group of patients with t(14;18) (p = 0.0001). The presence of t(14;18) was associated with favorable prognosis irrespective of either the mutation status of exon 16 in EZH2 or the FL grade. The analysis of the polymorphism rs2072407 status yielded the following genotypes: AA in 24 % (n = 19), AG in 42 % (n = 34), and GG in 34 % (n = 27) of cases. The variants АА and AG were associated with higher risk of death (hazard ratio 2.9; 95% confidence interval 1.2–10.6; p = 0.01), whereas the genotype GG was associated with wtEZH2 (10 % vs. 37 %) and favorable prognosis (p = 0.065).

Conclusion. Significant biological markers for favorable prognosis in FL appeared to be the presence of t(14;18)(q32;q21) and GG genotype of polymorphism rs2072407 in EZH2. The previously identified prognostic factors (grade 3А, bulky tumor lesions > 6 cm, Ki-67 > 35 %, and a short interval between symptom onset and chemotherapy start) were incorporated into a new unified personalized predictive (index PPI) FL model by supplementing it with two additional biological markers: the presence of t(14;18)(q32;q21) and GG genotype of polymorphism rs2072407. This approach may increase the prognostic value of the new personalized design which will provide the basis for risk-adapted algorithms for FL treatment.

Keywords: follicular lymphoma, prognosis, bulky, grades, Ki-67, t(14;18)(q32;q21), EZH2 gene.

Received: July 9, 2022

Accepted: November 30, 2022

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. 2016;127(20):2375–90. doi: 10.1182/blood‐2016‐01‐643569.
  2. Бабичева Л.Г., Поддубная И.В. Первая линия терапии индолентных неходжкинских лимфом в рутинной клинической практике. Современная онкология. 2020;22(2):119–25. doi: 10.26442/18151434.2020.2.200125.
    [Babicheva LG, Poddubnaya IV. First-line therapy of indolent non-Hodgkin’s lymphoma in routine clinical practice. Journal of Modern Oncology. 2020;22(2):119–25. doi: 10.26442/18151434.2020.2.200125. (In Russ)]
  3. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15(4):424–35. doi: 10.1016/S1470-2045(14)70027-0.
  4. Matasar MJ, Luminari S, Barr PM, et al. Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs. Oncologist. 2019;24(11):e1236–e1250. doi: 10.1634/theoncologist.2019-0138.
  5. Casulo C, Byrtek M, Dawson KL, et al. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516–22. doi: 10.1200/JCO.2014.59.7534.
  6. Casulo C, Day B, Dawson KL, et al. Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study. Ann Oncol. 2015;26(11):2311– doi: 10.1093/ annonc/mdv375.
  7. Smith A, Crouch S, Lax S, et al. Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Br J Cancer. 2015;112(9):1575–84. doi: 10.1038/bjc.2015.94.
  8. Bachy E, Houot R, Morschhauser F, et al. Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma. Haematologica. 2013;98(7):1107–14. doi: 10.3324/haematol.2012.082412.
  9. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–5. doi: 10.1038/ng.518.
  10. Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first‐line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population‐based registry. Lancet Oncol. 2015;16(9):1111– doi: 10.1016/ S1470‐2045(15)00169‐2.
  11. Carlotti E, Wrench D, Matthews J, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood. 2009;113(15):3553–7. doi: 10.1182/blood-2008-08-174839.
  12. Kridel R, Mottok A, Farinha P, et al. Cell of origin of transformed follicular lymphoma. Blood. 2015;126(18):2118–27. doi: 10.1182/blood-2015-06-649905.
  13. Dubois S, Mareschal S, Picquenot J-M, et al. Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: implications for targeted EZH2 inhibitor therapy? Oncotarget. 2015;6(18):16712–24. doi: 10.18632/oncotarget.3154.
  14. Huet S, Xerri L, Tesson B, et al. EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J. 2017;7(4):e555. doi: 10.1038/bcj.2017.32.
  15. Kridel R, Sehn LH, Gascoyne RD. Can histologic transformation of follicular lymphoma be predicted and prevented? Blood. 2017;130(3):258–66. doi: 10.1182/blood-2017-03-691345.
  16. Lossos IS, Alizadeh AA, Diehn M, et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci USA. 2002;99(13):8886–91. doi: 10.1073/pnas.132253599.
  17. Yap DB, Chu J, Berg T, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117(8):2451–9. doi: 10.1182/blood-2010-11-321208.
  18. Okosun J, Bodor C, Wang J, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46(2):176–81. doi: 10.1038/ng.2856.
  19. Beguelin W, Popovic R, Teater M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23(5):677–92. doi: 10.1016/j.ccr.2013.04.011.
  20. Caganova M, Carrisi C, Varano G, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013;123(12):5009–22. doi: 10.1172/JCI70626.
  21. Smith S. Transformed lymphoma: what should I do now? Hematology Am Soc Hematol Educ Program. 2020;2020(1):306–11. doi: 10.1182/hematology.2020000115.
  22. Cartron G, Trotman J. Time for an individualized approach to first-line management of follicular lymphoma. Haematologica. 2022;107(1):7–18. doi: 10.3324/haematol.2021.278766.
  23. Нестерова Е.С., Кравченко С.К., Мангасарова Я.К. и др. Фолликулярная лимфома. Высокодозная иммунохимиотерапия с трансплантацией аутологичных стволовых клеток крови: результаты первого проспективного исследования в России. Терапевтический архив. 2016;88(7):62–71. doi: 10.17116/terarkh201688762-71.
    [Nesterova ES, Kravchenko SK, Mangasarova YaK, et al. Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: Results of the first prospective study in Russia. Terapevticheskii arkhiv. 2016;88(7):62–71. doi: 10.17116/terarkh201688762-71. (In Russ)]
  24. Нестерова Е.С., Кравченко С.К., Ковригина А.М. и др. Фолликулярная лимфома: результаты многоцентрового исследования терапии первой линии препаратами бендамустин и ритуксимаб; факторы риска неблагоприятных событий (протокол FL-RUS-2013). Онкогематология. 2018;13(3):10–24. doi: 10.17650/1818-8346-2018-13-3-10-24.
    [Nesterova ES, Kravchenko SK, Kovrigina AM, et al. Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab; risk factors for adverse events (FL-RUS-2013 protocol). Oncohematology. 2018;13(3):10–24. doi: 10.17650/1818-8346-2018-13-3-10-24. (In Russ)]
  25. Нестерова Е.С., Кравченко С.К., Барях Е.А. и др. Трансплантация аутологичных стволовых клеток крови в первой ремиссии фолликулярной лимфомы как «терапия спасения» пациентов с факторами неблагоприятного прогноза. Результаты первого проспективного исследования. Современная онкология. 2016;18(5):31–2. doi: 10.26442/1815-1434_2016.5.31-32.
    [Nesterova ES, Kravchenko SK, Baryah EA, et al. Autologous stem cells transplantation in the first remission of follicular lymphoma as “rescue therapy” in patients with unfavorable prognosis factors. The first prospective study results. Journal of Modern Oncology. 2016;18(5):31–2. doi: 10.26442/1815-1434_2016.5.31-32. (In Russ)]
  26. Нестерова Е.С., Кравченко С.К., Ковригина А.М. и др. Фолликулярная лимфома: критерии выбора терапии первой линии. Терапевтический архив. 2019;91(8):75–83. doi: 10.26442/00403660.2019.08.000388.
    [Nesterova ES, Kravchenko SK, Kovrigina AM, et al. Follicular lymphoma: first-line selection criteria of treatment. Terapevticheskii arkhiv. 2019;91(8):75–83. doi: 10.26442/00403660.2019.08.000388. (In Russ)]
  27. Rummel MJ, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. J Clin Oncol. 2017;35(15_suppl):7501. doi: 10.1200/JCO.2017.35.15_suppl.7501.
  28. Нестерова Е.С., Яцык Г.А., Луцик Н.С. и др. Информативность диффузионно-взвешенной магнитно-резонансной томографии всего тела и позитронно-эмиссионной томографии с компьютерной томографией при фолликулярной лимфоме. Терапевтический архив. 2020;92(7):55–62. doi: 10.26442/00403660.2020.07.000774.
    [Nesterova ES, Yatsyk GA, Lutsik NS, et al. Informativeness of whole-body diffusion-weighted magnetic resonance imaging and positron emission tomography with computed tomography in follicular lymphoma. Terapevticheskii arkhiv. 2020;92(7):55–62. doi: 10.26442/00403660.2020.07.000774. (In Russ)]
  29. Knutson SK, Kawano S, Minoshima Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13(4):842–54. doi: 10.1158/1535-7163.MCT-13-0773.
  30. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055–63. doi: 10.1182/blood-2015-11-624288.
  31. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open‐label, single‐arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433–42. doi: 10.1016/S1470‐2045(20)30441‐1.
  32. Fischer T, Zing NPC, Chiattone CS, et al. Transformed follicular lymphoma. Ann Hematol. 2018;97(1):17–29. doi: 10.1007/s00277-017-3151-2.