Analysis of genetic aberrations in pediatric high-grade gliomas

Background. High-grade gliomas are characterized by a wide range of genetic abnormalities. The heterogeneous genomic landscape of pediatric high-grade gliomas allows identifying distinct subgroups of the disease in children and young adults. Most importantly, these subgroups differ by clinical course and prognosis, as well as treatment response to standard therapy.

Objective: to assess the profile of molecular genetic markers of high-grade gliomas in children.

Materials and methods. In the current study, we examine the frequency of H3F3A, Hist1H3B, BRAF, IDH1 / 2 mutations, the copy number alterations of CDKN2A / 2B genes and the expression of ETV6‑NTRK3 fusion gene in a cohort of 53 pediatric high-grade gliomas.

Results. Driver mutations and CDKN2A / 2B deletions were observed in 24 (45 %) and 15 (28 %) of 53 tumors, respectively. Overall, the studied high-grade gliomas harbored 41 genetic aberrations including 24 (58.5 %) somatic missense mutations, 1 (2.4 %) genetic variant of unknown clinical significance, 1 (2.4 %) oncogenic fusion gene and 15 (36.6 %) deletions of the tumor suppressor genes.

Conclusion. These findings point to the importance of molecular profiling of tumors for the optimal clinical care and development of new approaches to treatment aimed at molecular targets for personalized anticancer therapies.

1. Louis D.N., Perry A., Reifenberger G. et al. The 2016 World Health Organization classification of tumors of the Central Nervous System: a summary. Acta Neuropathol 2016;131:803–20. DOI: 10.2176/nmc.ra.2017-0010.

2. Johnson A., Severson E., Gay L. et al. Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumor mutational burden, and hypermutation signatures. Oncologist 2017;22(12):1478–90. DOI: 10.1634/theoncologist.2017-0242.

3. Zaytseva M.A., Yasko L.A., Papusha L.I., Druy A.E. Molecular genetic features of pediatric gliomas. Voprosy gematologii/ onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology 2019;18(4):109–17. (In Russ.) DOI: 10.24287/1726-1708-2019-18-4-109-117.

4. Gambella A., Senetta R., Collemi G. et al. NTRK fusions in central nervous system tumors: a rare, but worthy target. Int J Mol Sci 2020;21(3):753. DOI: 10.3390/ijms21030753.

5. Toll S.A., Tran H.N., Cotter J. et al. Sustained response of three pediatric BRAFV600E mutated high-grade gliomas to combined BRAF and MEK inhibitor therapy. Oncotarget 2019;10(4):551–7. DOI: 10.18632/oncotarget.26560.

6. Catalogue of somatic mutations in cancer. Available at: https://cancer.sanger.ac.uk/cosmic.

7. Leske H., Rushing E., Budka H. et al. K27/G34 versus K28/G35 in histone H3-mutant gliomas: a note of caution. Acta Neuropathologica 2018;136(1):175–6. DOI: 10.1007/s00401-018-1867-2.

8. Grigore F.N., Day C., Yang H. et al. Histone H3.3 mutations drive tumorigenesis through chromosomal instability. Neurooncology 2019;21(Suppl_2):ii84. DOI: 10.1093/neuonc/noz036.086.

9. Maeda S., Ohka F., Okuno Y. et al. H3F3A mutant allele specific imbalance in an aggressive subtype of diffuse midline glioma, H3 K27M-mutant. Acta Neuropathol Commun 2020;8(1):8. DOI:10.1186/s40478-020-0882-4.

10. Solomon D.A., Wood M.D., Tihan T. et al. Diffuse midline gliomas with histone H3 K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 2016;26(5):569–80. DOI: 10.1111/bpa.12336.

11. Phillips J.J., Gong H., Chen K. et al. The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. Brain Pathol 2019;29(1):85–96. DOI: 10.1111/bpa.12639.

12. Vaubel R.A., Caron A.A., Yamada S. et al. Recurrent copy number alterations in lowgrade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. Brain Pathol 2018;28(2): 172–82. DOI: 10.1111/bpa.12495.

13. Touat M., Younan N., Euskirchen P. et al. Successful targeting of an ATG7-RAF1 gene fusion in anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination. JCO Precis Oncol 2019;3:1–7. DOI: 10.1200/PO.18.00298.

14. Frazão L., do Carmo Martins M., Nunes V.M. et al. BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co- deletions – markers in the clinical stratification of pediatric gliomas. BMC Cancer 2018;18(1):1259. DOI: 10.1186/s12885-018-5120-0.

15. Rajbhandari R., McFarland B.C., Patel A. et al. Loss of tumor suppressive microRNA- 31 enhances TRADD/NF-κB signaling in glioblastoma. Oncotarget 2015;6(19):17805–16. DOI: 10.18632/oncotarget.4596.

16. Pollack I.F., Hamilton R.L., Sobol R.W. et al. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Child’s Nervous System 2011;27(1):87–94. DOI: 10.1007/s00381-010-1264-1.

17. Buccoliero A.M., Castiglione F., Degl’Innocenti D.R. et al. IDH1 mutation in pediatric gliomas: has it a diagnostic and prognostic value? Fetal Pediatr Pathol 2012;31:278–82. DOI: 10.3109/15513815.2012.659383.

18. Antonelli M., Buttarelli F.R., Arcella A. et al. Prognostic significance of histological grading, p53 status, YKL-40 expression, and IDH1 mutations in pediatric high-grade gliomas. J Neurooncol 2010;99:209–15. DOI: 10.1007/s11060-010-0129-5.

19. Guerreiro Stucklin A.S., Ryall S., Fukuoka K. et al. Alterations in ALK/ ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun 2019;10(1):4343. DOI: 10.1038/s41467-019-12187-5.

20. Desai A.V., Robinson G.W., Basu E.M. et al. Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors. J Clin Oncol

21. ;38(15_suppl):107. DOI: 10.1200/JCO.2020.38.15_suppl.107.