Primary mediastinal large B-cell lymphoma with a rare ALK gene mutation

Introduction. Primary mediastinal large B-cell lymphoma is an aggressive variant of lymphoma characterized by genetic heterogeneity. First-time therapy for primary mediastinal large B-cell lymphoma usually includes immunochemotherapy. However, a substantial proportion of patients do not respond to this therapy.

Objective – to analyze clinical characteristics of primary refractory primary mediastinal large B-cell lymphoma taking into account the results of targeted next-generation sequencing (NGS).

Materials and methods. A 22‑year-old patient with primary mediastinal large B-cell lymphoma who had not responded to immunochemotherapy was tested using targeted NGS for 77 genes.

Results. We identified 2 rare mutations in the ALK gene with an unclear clinical value. According to the literature, these mutations are primarily found in solid tumors.

Conclusion. Missense mutations identified in the ALK gene are presumably associated with the course of primary mediastinal large B-cell lymphoma, in particular, with primary refractory disease.

1. Arkhipova O.E., Chernogubova E.A., Tarasov V.A. et al. The level of oncological diseases as an indicator of the medical and environmental safety of territories (on the example of the Rostov region). Vestnik Yuzhnogo nauchnogo centra RAN = Bulletin of the Southern Scientific Center of the Russian Academy of Sciences 2013;9(3):7–14. (In Russ.).

2. Kamaeva I.A., Lysenko I.B., Nikolaeva N.V. et al. The use of immunotherapy for the treatment of refractory forms of Hodgkin’s lymphoma in real clinical practice. Yuzhno-Rossijskij onkologicheskij zhurnal = South Russian Journal of Oncology 2021;2(2):34–41. (In Russ.). DOI: 10.37748/2686-9039-2021-2-2-4.

3. Li M.M., Datto M., Duncavage E.J. et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 2017;19(1):4–23. DOI: 10.1016/j.jmoldx.2016.10.002.

4. Taghizadeh H., Müllauer L., Mader R.M., Schindl M., Prager G.W. Applied precision medicine in metastatic pancreatic ductal adenocarcinoma. Ther Adv Med Oncol 2020;12:1758835920938611. DOI: 10.1177/1758835920938611.

5. NCBI. ALK receptor tyrosine kinase [Homo sapiens (human)]. Available at: https://www.ncbi.com.

6. Wang H., Wang Z., Zhang G. et al. Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC: EGFR, ALK, and RET gene mutations. Cancer Med 2020;9(2):487–95. DOI: 10.1002/cam4.2706.

7. Majewska H., Gorczyński A., Czapiewski P. et al. ALK alterations in salivary gland carcinomas. Virchows Arch 2021;478(5):933–41. DOI: 10.1007/s00428-020-02971-w.

8. ALK Pathway. Gene Set Enrichment Analysis. Available at: https://www.gseamsigdb.org/gsea/index.jsp.

9. Genetics illustrations. Smart Servier Medical Art.Available at: https://smart.servier.com/category/cellular-biology/genetics/.

10. Ronchi A., Montella M., Cozzolino I. et al. The potential diagnostic and predictive role of anaplastic lymphoma kinase (ALK) gene alterations in melanocytic tumors. Eur Rev Med Pharmacol Sci 2020;24(7):3829–38. DOI: 10.26355/eurrev_202004_20849.

11. Kazlouskaya V., Ho J., Jedrych J., Karunamurthy A. Spindle cell variant of epithelioid cell histiocytoma (spindle cell histiocytoma) with ALK gene fusions: cases series and review of the literature. J Cutan Pathol 2021;48(7):837–41. DOI: 10.1111/cup.13923.

12. Yang C., Zhang L., Love-Gregory L. et al. Identification of novel ALK rearrangements in gynecologic clear cell carcinoma. Int J Cancer 202115;148(2):459–68. DOI: 10.1002/ijc.33330.

13. Fetahu I.S., Taschner-Mandl S. Neuroblastoma and the epigenome. Cancer Metastasis Rev 2021;40(1):173–89. DOI: 10.1007/s10555-020-09946-y.

14. Berry T., Luther W., Bhatnagar N. et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 2012;22(1):117–30. DOI: 10.1016/j.ccr.2012.06.001.

15. Umapathy G., Mendoza-Garcia P., Hallberg B., Palmer R.H. Targeting anaplastic lymphoma kinase in neuroblastoma. APMIS 2019;127(5):288–302. DOI: 10.1111/apm.12940.

16. Mossé Y.P., Laudenslager M., Longo L. et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 2008;455(7215):930–5. DOI: 10.1038/nature07261.

17. Mlakar V., Morel E., Mlakar S.J. et al. A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma. J Exp Clin Cancer Res 2021;40(1):189. DOI: 10.1186/s13046-021-01967-x.

18. 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: 10.1007/s00401-016-1545-1.

19. Hadjadj J., Castro C.N., Tusseau M. et al. Early-onset autoimmunity associated with SOCS1 haploinsufficiency. Nat Commun 2020;11(1):5341. DOI: 10.1038/s41467-020-18925-4.

20. Chapuy B., Stewart C., Dunford A.J. et al. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood 2019;134(26):2369–82. DOI: 10.1182/blood.2019002067.

21. Dubois S., Viailly P.J., Mareschal S. et al. Next-generation sequencing in diffuse large B-cell lymphoma highlights molecular divergence and therapeutic opportunities: a LYSA study. Clin Cancer Res 2016;22(12):2919–28. DOI: 10.1158/1078-0432.CCR-15-2305.

22. Zhou H., Xu-Monette Z.Y., Xiao L. et al. Prognostic factors, therapeutic approaches, and distinct immunobiologic features in patients with primary mediastinal large B-cell lymphoma on long-term follow-up. Blood Cancer J 2020;10(5):49. DOI: 10.1038/s41408-020-0312-7.