Клинические аспекты молекулярно-генетического тестирования в детской онкологии

Онкологические заболевания занимают лидирующие позиции в структуре детской смертности, несмотря на значительные успехи в их лечении. Летальность может быть обусловлена не только прогрессированием основного заболевания ввиду резистентности опухоли к проводимой терапии, но и лекарственно-индуцированной токсичностью, и инфекционными осложнениями. Использование новых диагностических технологий, способствующих выявлению клинически значимых молекулярно-генетических альтераций в опухоли, делает возможным индивидуальный подход к выбору терапии с целью повышения ее эффективности и снижения токсичности, а таже улучшения качества жизни пациентов и их семей в период проведения специфического лечения. Наиболее перспективными диагностическими тестами в указанном аспекте являются разновидности секвенирования нового поколения: широкопанельное таргетное, полноэкзомное и полногеномное секвенирование опухолевого материала и лейкоцитарной ДНК пациента. Несмотря на относительную редкость выявляемых патогенных генетических альтераций, ряд из них имеют прогностическую значимость, определяют чувствительность к противоопухолевому лечению, а также являются мишенями для проведения направленной терапии. При этом последняя при ряде нозологий демонстрирует преимущества по сравнению со стандартными методами лечения. Тем не менее применение противоопухолевых препаратов таргетного механизма действия в педиатрической популяции сопряжено с рядом ограничений по сравнению со взрослым населением. В первую очередь это обусловлено отсутствием утвержденных доз, режимов и показаний к применению для большей части новых лекарственных препаратов, рисками развития нежелательных явлений, а также их высокой стоимостью. В статье представлены актуальные вопросы клинического применения таргетной терапии в онкопедиатрии на основании данных молекулярно-генетической диагностики.

1. Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F et al. International incidence of childhood cancer, 2001–2010: a population-based registry study. Lancet Oncol. 2017;18(6):719–731. https://doi.org/10.1016/s1470-2045(17)30186-9.

2. Lam CG, Howard SC, Bouffet E, Pritchard-Jones K. Science and health for all children with cancer. Science. 2019;363(6432):1182–1186. https://doi.org/10.1126/science.aaw4892.

3. Loeffen EAH, Knops RRG, Boerhof J, Feijen EAML, Merks JHM, Reedijk AMJ et al. Treatment-related mortality in children with cancer: Prevalence and risk factors. Eur J Cancer. 2019;121:113–122. https://doi.org/10.1016/j.ejca.2019.08.008.

4. Elzagallaai AA, Carleton BC, Rieder MJ. Pharmacogenomics in Pediatric Oncology: Mitigating Adverse Drug Reactions While Preserving Efficacy. Annu Rev Pharmacol Toxicol. 2021;61:679–699. https://doi.org/10.1146/annurev-pharmtox-031320-104151.

5. Forrest SJ, Geoerger B, Janeway KA. Precision medicine in pediatric oncology. Curr Opin Pediatr. 2018;30(1):17–24. https://doi.org/10.1097/MOP.0000000000000570.

6. Lee J, Gillam L, Visvanathan K, Hansford JR, McCarthy MC. Clinical Utility of Precision Medicine in Pediatric Oncology: A Systematic Review. JCO Precis Oncol. 2021;(5):1088–1102. https://doi.org/10.1200/PO.20.00405.

7. Kline CN, Joseph NM, Grenert JP, van Ziffle J, Talevich E, Onodera C et al. Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro Oncol. 2017;19(5):699–709. https://doi.org/10.1093/neuonc/now254.

8. Zhong Y, Xu F, Wu J, Schubert J, Li MM. Application of Next Generation Sequencing in Laboratory Medicine. Ann Lab Med. 2021;41(1):25–43. https://doi.org/10.3343/alm.2021.41.1.25.

9. Barsan V, Paul M, Gorsi H, Malicki D, Elster J, Kuo DJ, Crawford J. Clinical Impact of Next-generation Sequencing in Pediatric Neuro-Oncology Patients: A Single-institutional Experience. Cureus. 2019;11(12):e6281. https://doi.org/10.7759/cureus.6281.

10. Ahmed AA, Vundamati DS, Farooqi MS, Guest E. Precision Medicine in Pediatric Cancer: Current Applications and Future Prospects. High Throughput. 2018;7(4):39. https://doi.org/10.3390/ht7040039.

11. Hill RM, Richardson S, Schwalbe EC, Hicks D, Lindsey JC, Crosier S et al. Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. Lancet Child Adolesc Health. 2020;4(12):865–874. https://doi.org/10.1016/S2352-4642(20)30246-7.

12. Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M et al. Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes. Acta Neuropathol. 2019;138(2):309–326. https://doi.org/10.1007/s00401-019-02020-0.

13. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29(11):1408–1414. https://doi.org/10.1200/JCO.2009.27.4324.

14. Simon T, Hero B, Schulte JH, Deubzer H, Hundsdoerfer P, von Schweinitz D et al. 2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors. Klin Padiatr. 2017;229(3):147–167. https://doi.org/10.1055/s-0043-103086.

15. Lee JW, Cho B. Prognostic factors and treatment of pediatric acute lymphoblastic leukemia. Korean J Pediatr. 2017;60(5):129–137. https://doi.org/10.3345/kjp.2017.60.5.129.

16. Ramkissoon SH, Bandopadhayay P, Hwang J, Ramkissoon LA, Greenwald NF, Schumacher SE et al. Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors. Neuro Oncol. 2017;19(7):986–996. https://doi.org/10.1093/neuonc/now294.

17. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231–1251. https://doi.org/10.1093/neuonc/noab106.

18. Trubicka J, Grajkowska W, Dembowska-Bagińska B. Molecular Markers of Pediatric Solid Tumors-Diagnosis, Optimizing Treatments, and Determining Susceptibility: Current State and Future Directions. Cells. 2022;11(7):1238. https://doi.org/10.3390/cells11071238.

19. Mosaab A, El-Ayadi M, Khorshed EN, Amer N, Refaat A, El-Beltagy M et al. Histone H3K27M Mutation Overrides Histological Grading in Pediatric Gliomas. Sci Rep. 2020;10(1):8368. https://doi.org/10.1038/s41598-020-65272-x.

20. Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A. 2017;173(4):1017–1037. https://doi.org/10.1002/ajmg.a.38142.

21. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015;373(24):2336–2346. https://doi.org/10.1056/NEJMoa1508054.

22. Суспицын ЕН, Имянитов ЕН. Наследственные заболевания, ассоциированные с повышенным риском развития опухолей детского возраста. Биохимия. 2023;88(7):1085–1100. https://doi.org/10.31857/S0320972523070035.

23. Kratz CP, Achatz MI, Brugières L, Frebourg T, Garber JE, Greer MC et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin Cancer Res. 2017;23(11):e38–e45. https://doi.org/10.1158/1078-0432.CCR-17-0408.

24. Waanders E, Gu Z, Dobson SM, Antić Ž, Crawford JC, Ma X et al. Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia. Blood Cancer Discov. 2020;1(1):96–111. https://doi.org/10.1158/0008-5472.BCD-19-0041.

25. Yang F, Brady SW, Tang C, Sun H, Du L, Barz MJ et al. Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse. Nat Cancer. 2021;2(8):819–834. https://doi.org/10.1038/s43018-021-00230-8.

26. Kratz CP, Jongmans MC, Cavé H, Wimmer K, Behjati S, Guerrini-Rousseau L et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc Health. 2021;5(2):142–154. https://doi.org/10.1016/S2352-4642(20)30275-3.

27. Laetsch TW, DuBois SG, Bender JG, Macy ME, Moreno L. Opportunities and Challenges in Drug Development for Pediatric Cancers. Cancer Discov. 2021;11(3):545–559. https://doi.org/10.1158/2159-8290.CD-20-0779.

28. Baudino TA. Targeted Cancer Therapy: The Next Generation of Cancer Treatment. Curr Drug Discov Technol. 2015;12(1):3–20. https://doi.org/10.2174/1570163812666150602144310.

29. Mody RJ, Prensner JR, Everett J, Parsons DW, Chinnaiyan AM. Precision medicine in pediatric oncology: Lessons learned and next steps. Pediatr Blood Cancer. 2017;64(3):e26288. https://doi.org/10.1002/pbc.26288.

30. Schramm A, Köster J, Assenov Y, Althoff K, Peifer M, Mahlow E et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet. 2015;47(8):872–877. https://doi.org/10.1038/ng.3349.

31. Preobrazhenskaya EV, Suleymanova AM, Bizin IV, Zagrebin FA, Romanko AA, Saitova ES et al. Spectrum of kinase gene rearrangements in a large series of paediatric inflammatory myofibroblastic tumours. Histopathology. 2023;83(1):109–115. https://doi.org/10.1111/his.14912.

32. Li S, Lai M, Cai L. LGG-36. Analysis of BRAF-related mutations in pediatric low-grade glioma. Neuro Oncol. 2022;24(Suppl. 1):i96. https://doi.org/10.1093/neuonc/noac079.348.

33. Talloa D, Triarico S, Agresti P, Mastrangelo S, Attinà G, Romano A et al. BRAF and MEK Targeted Therapies in Pediatric Central Nervous System Tumors. Cancers (Basel). 2022;14(17):4264. https://doi.org/10.3390/cancers14174264.

34. Berlanga P, Pierron G, Lacroix L, Chicard M, Adam de Beaumais T, Marchais A et al. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies. Cancer Discov. 2022;12(5):1266–1281. https://doi.org/10.1158/2159-8290.CD-21-1136.

35. Ecker J, Selt F, Sturm D, Sill M, Korshunov A, Hirsch S et al. Molecular diagnostics enables detection of actionable targets: the Pediatric Targeted Therapy 2.0 registry. Eur J Cancer. 2023;180:71–84. https://doi.org/10.1016/j.ejca.2022.11.015.

36. Ziegler D, Lau L, Khuong-Quang DA, Mayoh C, Wong M, Barahona P et al. Precision-guided treatment improves outcomes for children with high-risk cancers. Research Square. 2023. https://doi.org/10.21203/rs.3.rs-3376668/v1.

37. Strzebonska K, Wasylewski MT, Zaborowska L, Polak M, Slugocka E, Stras J et al. Risk and Benefit for Targeted Therapy Agents in Pediatric Phase II Trials in Oncology: A Systematic Review with a Meta-Analysis. Target Oncol. 2021;16(4):415–424. https://doi.org/10.1007/s11523-021-00822-5.

38. Nelson MR, Johnson T, Warren L, Hughes AR, Chissoe SL, Xu CF, Waterworth DM. The genetics of drug efficacy: opportunities and challenges. Nat Rev Genet. 2016;17(4):197–206. https://doi.org/10.1038/nrg.2016.12.

39. Van Tilburg CM, Pfaff E, Pajtler KW, Langenberg KPS, Fiesel P, Jones BC et al. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets. Cancer Discov. 2021;11(11):2764–2779. https://doi.org/10.1158/2159-8290.CD-21-0094.

40. Church AJ, Corson LB, Kao PC, Imamovic-Tuco A, Reidy D, Doan D et al. Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer. Nat Med. 2022;28(8):1581–1589. https://doi.org/10.1038/s41591-022-01856-6.

41. Burdach SEG, Westhoff MA, Steinhauser MF, Debatin KM. Precision medicine in pediatric oncology. Mol Cell Pediatr. 2018;5(1):6. https://doi.org/10.1186/s40348-018-0084-3.

42. Butler E, Ludwig K, Pacenta HL, Klesse LJ, Watt TC, Laetsch TW. Recent progress in the treatment of cancer in children. CA Cancer J Clin. 2021;71(4):315–332. https://doi.org/10.3322/caac.21665.

43. Marayati R, Quinn CH, Beierle EA. Immunotherapy in Pediatric Solid Tumors-A Systematic Review. Cancers (Basel). 2019;11(12):2022. https://doi.org/10.3390/cancers11122022.

44. Long AH, Morgenstern DA, Leruste A, Bourdeaut F, Davis KL. Checkpoint Immunotherapy in Pediatrics: Here, Gone, and Back Again. Am Soc Clin Oncol Educ Book. 2022;42:1–14. https://doi.org/10.1200/EDBK_349799.

45. Chang H, Sasson A, Srinivasan S, Golhar R, Greenawalt DM, Geese WJ et al. Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small-Cell Lung Cancer. Mol Diagn Ther. 2019;23(4):507–520. https://doi.org/10.1007/s40291-019-00408-y.

46. Wu HX, Wang ZX, Zhao Q, Wang F, Xu RH. Designing gene panels for tumor mutational burden estimation: the need to shift from ‘correlation’ to ‘accuracy’. J Immunother Cancer. 2019;7(1):206. https://doi.org/10.1186/s40425-019-0681-2.

47. Noskova H, Kyr M, Pal K, Merta T, Mudry P, Polaskova K et al. Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision? Cancers (Basel). 2020;12(1):230. https://doi.org/10.3390/cancers12010230.

48. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–218. https://doi.org/10.1038/nature12213.

49. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R et al. Comprehensive Analysis of Hypermutation in Human Cancer. Cell. 2017;171(5):1042–1056.e10. https://doi.org/10.1016/j.cell.2017.09.048.

50. Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, Vezina C, Pappo A et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1–2 trial. Lancet Oncol. 2020;21(1):121–133. https://doi.org/10.1016/S1470-2045(19)30671-0.