Спектр синдромов избыточного роста, ассоциированных с мутацией PIK3CA: молекулярный механизм, особенности диагностики и терапии

Постзиготические соматические варианты в генах, ассоциированных с развитием опухолей, лежат в основе ряда синдромов, проявляющихся избыточным ростом и сосудистыми мальформациями. Одним из ключевых заболеваний этой группы является спектр синдромов избыточного роста, ассоциированный с PIK3CA (PROS – PIK3CA-related overgrowth spectrum), объединяющий более 20 состояний, характеризующихся асимметричным избыточным ростом и сосудистыми мальформациями. Ген PIK3CA кодирует каталитическую субъединицу p110α фосфатидилинозитол-3-киназы и подвергается мутациям при различных видах рака. Мутационные события при PROS происходят на этапе эмбрионального развития, приводя к мозаичному распределению мутаций. Разнообразие и тяжесть клинических проявлений PROS определяются комбинацией ряда факторов, включая степень активации PI3K конкретным вариантом, тип пораженной ткани, момент появления мутации и влияние дополнительных факторов. Высокая фенотипическая вариабельность PROS, сходство с другими синдромами избыточного роста и сосудистых мальформаций и особенности молекулярно-генетической диагностики мозаичных вариантов затрудняют диагностику синдрома. В данном обзоре обобщены имеющиеся знания о молекулярном механизме PROS, участии регуляторной субъединицы в патогенезе PROS, а также обсуждены особенности диагностики и терапии этого заболевания.

1. Keppler-Noreuil K.M., Rios J.J., Parker V.E.R., et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167A(2):287–295.

2. Reynolds G., Cardaropoli S., Carli D., et al. Epidemiology of the disorders of the Pik3ca-related overgrowth spectrum (Pros). Eur J Hum Genet. 2023;31(11):1333–1336.

3. Kuentz P., St-Onge J., Duffourd Y., et al. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. Genet Med. 2017;19(9):989–997.

4. Mussa A., Leoni C., Iacoviello M., et al. Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants. J Med Genet. 2023;60(2):163–173.

5. Singh S., Bradford D., Li X., et al. FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum. Clin Cancer Res. 2024;30(1):23–28.

6. Fruman D.A., Chiu H., Hopkins B.D., et al. The PI3K pathway in human disease. Cell. 2017 10;170(4):605–635.

7. Fox M., Mott H.R., Owen D. Class IA PI3K regulatory subunits: p110-independent roles and structures. Biochem Soc Trans. 2020; 48(4):1397–1417.

8. Wang S., Wang W., Zhang X., et al. A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation. Orphanet J Rare Dis. 2021;16(1):208.

9. Liu S., Knapp S., Ahmed A.A. The structural basis of PI3K cancer mutations: from mechanism to therapy. Cancer Res. 2014;74(3):641–646.

10. Cottrell C.E., Bender N.R., Zimmermann M.T., et al. Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth. Genet Med. 2021;23(10):1882–1888.

11. Madsen R.R., Vanhaesebroeck B., Semple R.K. Cancer-Associated PIK3CA Mutations in Overgrowth Disorders. Trends Mol Med. 2018;24(10):856–870.

12. Morin G.M., Zerbib L., Kaltenbach S., et al. PIK3CA-Related Disorders: From Disease Mechanism to Evidence-Based Treatments. Annu Rev Genomics Hum Genet. 2024;25(1):211–237.

13. Angulo-Urarte A., Graupera M. When, where and which PIK3CA mutations are pathogenic in congenital disorders. Nat Cardiovasc Res. 2022;1(8):700-714.

14. Canaud G., Hammill A.M., Adams D., et al. A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations. Orphanet J Rare Dis. 2021;16(1):306.

15. Keppler-Noreuil K.M. Lozier J., Oden N., et al. Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):571–581.

16. Martinez-Glez V., Rodriguez-Laguna L., Viana-Huete V., et al. Segmental undergrowth is associated with pathogenic variants in vascular malformation genes: A retrospective case-series study. Clin Genet. 2022;101(3):296–306.

17. Peyre M., Miyagishima D., Bielle F., et al. Somatic PIK3CA mutations in sporadic cerebral cavernous malformations. N Engl J Med. 2021;385(11):996–1004.

18. De Bortoli M., Queisser A., Pham V.C., et al. Somatic Loss-of-Function PIK3R1 and Activating Non-hotspot PIK3CA Mutations Associated with Capillary Malformation with Dilated Veins (CMDV). J Invest Dermatol. 2024;144(9):2066-2077.

19. Kuentz P., Engel C., Laeng M., et al. Clinical phenotype of the PIK3R1-related vascular overgrowth syndrome. Br J Dermatol. 2024;191(2):303–305.

20. Schönewolf-Greulich B., Karstensen H.G., Hjortshøj T.D., et al. Early diagnosis enabling precision medicine treatment in a young boy with PIK3R1-related overgrowth. Eur J Med Genet. 2022;65(10):104590.

21. Mirzaa G., Timms A.E., Conti V., et al. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight. 2016;1(9).

22. Kobialka P., Sabata H., Vilalta O., et al. The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib. EMBO Mol Med. 2022;14(7):e15619.

23. Kurek K.C., Luks V.L., Ayturk U.M., et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012;90(6):1108–1115.

24. Martinez-Corral I., Zhang Y., Petkova M., et al. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation. Nat Commun. 2020;11(1):2869.

25. Chen H., Sun B., Liu H., et al. Delineation of the phenotypes and genotypes of PIK3CA-related overgrowth spectrum in East asians. Mol Genet Genomics. 2024;299(1):66.

26. Mojarad B.A., Hernandez P.V., Evenson M.J., et al. Profiling PIK3CA variants in disorders of somatic mosaicism. Genetics in Medicine Open. 2023;1(1):100815.

27. Dogruluk T., Tsang Y.H., Espitia M., et al. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. Cancer Res. 2015;75(24):5341–5354.

28. Jansen L.A., Mirzaa G.M., Ishak G.E., et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain. 2015;138(Pt 6):1613–1628.

29. Cao Y., Evenson M.J., Corliss M.M., et al. Co-existence of 2 clinically significant variants causing disorders of somatic mosaicism. Genetics in Medicine Open. 2023;1(1):100807.

30. Dewar J., Lomas D., O’Neill C., et al. PA04 Germline activating variants in PIK3CA result in a diffuse overgrowth phenotype characterized by macrocephaly, cardiovascular and renal anomalies: recommendations for screening and monitoring. British Journal of Dermatology. 2024;191(Supplement_1):i124–i124.

31. Cooley Coleman J.A., Gass J.M., Srikanth S., et al. Clinical and functional characterization of germline PIK3CA variants in patients with PIK3CA-related overgrowth spectrum disorders. Hum Mol Genet. 2023;32(9):1457–1465.

32. Wilke M.V.M.B., Schimmenti L., Lopour M.Q.R., et al. A somatic splice-site variant in PIK3R1 in a patient with vascular overgrowth and low immunoglobulin levels: A case report. Mol Genet Genomic Med. 2023;11(12):e2271.

33. Goss J.A., Konczyk D.J., Smits P., et al. Diffuse capillary malformation with overgrowth contains somatic PIK3CA variants. Clin Genet. 2020;97(5):736–740.

34. Diociaiuti A., Rotunno R., Pisaneschi E., et al. Clinical and Molecular Spectrum of Sporadic Vascular Malformations: A Single-Center Study. Biomedicines. 2022;10(6).

35. Al-Olabi L., Polubothu S., Dowsett K., et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. The Journal of Clinical Investigation. 2018;128(4):1496-1508.

36. Queisser A., Seront E., Boon L.M., Vikkula M. Genetic basis and therapies for vascular anomalies. Circ Res. 2021;129(1):155–173.

37. Venot Q., Blanc T., Rabia S.H., et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018;558(7711):540–546.

38. Valentini V., Zelli V., Rizzolo P., et al. PIK3CA c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report. Clin Case Rep. 2018;6(7):1358–1363.

39. Youssefian L., Vahidnezhad H., Baghdadi T., et al. Fibroadipose hyperplasia versus Proteus syndrome: segmental overgrowth with a mosaic mutation in the PIK3CA gene. J Invest Dermatol. 2015;135(5):1450–1453.

40. McNulty S.N., Evenson M.J., Corliss M.M., et al. Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort. Am J Hum Genet. 2019;105(4):734–746.

41. Mussa A., Carli D., Cardaropoli S, et al. Lateralized and segmental overgrowth in children. Cancers (Basel). 2021;13(24):6166.

42. Zhou X.P., Marsh D.J., Hampel H., et al. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet. 2000;9(5):765–768.

43. Caux F., Plauchu H., Chibon F., et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur J Hum Genet. 2007;15(7):767–773.

44. Castel P., Carmona F.J., Grego-Bessa J., et al. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med. 2016;8(332):332ra42.

45. Limaye N., Kangas J., Mendola A., et al. Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet. 2015;97(6):914–921.

46. Zerbib L., Ladraa S., Fraissenon A., et al. Targeted therapy for capillary-venous malformations. Signal Transduct Target Ther. 2024;9(1):146.

47. Siegel D.H., Cottrell C.E., Streicher J.L., et al. Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics. J Invest Dermatol. 2018;138(4):957–967.

48. Ten Broek R.W., Eijkelenboom A., van der Vleuten C.J..M, et al. Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases. Genes Chromosomes Cancer. 2019;58(8):541–550.

49. Claire Hou Y.-C., Evenson M.J., Corliss M.M., et al. A comparative analysis of RAS variants in patients with disorders of somatic mosaicism. Genet Med. 2023;25(3):100348.

50. Chang C.A., Perrier R., Kurek K.C., et al. Novel findings and expansion of phenotype in a mosaic RASopathy caused by somatic KRAS variants. Am J Med Genet A. 2021;185(9):2829–2845.

51. Schmidt V.F., Wieland I., Wohlgemuth W..A, et al. Mosaic RASopathy due to KRAS variant G12D with segmental overgrowth and associated peripheral vascular malformations. Am J Med Genet A. 2021;185(10):3122–3128.

52. Chagas C.A.A., Pires L.A.S., Babinski M.A., Leite T.F. de O. Klippel-Trenaunay and Parkes-Weber syndromes: two case reports. J vasc bras. 2017;16(4):320–324.

53. Peterman C.M., Fevurly R.D., Alomari A.I., et al. Sonographic screening for Wilms tumor in children with CLOVES syndrome. Pediatr Blood Cancer. 2017;64(12).

54. Blatt J., Finger M., Price V., et al. Cancer Risk in Klippel-Trenaunay Syndrome. Lymphat Res Biol. 2019;17(6):630–636.

55. Faivre L., Crépin J.-C., Réda M., et al. Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations. Clin Genet. 2023;104(5):554–563.

56. Lalonde E., Ebrahimzadeh J., Rafferty K., et al. Molecular diagnosis of somatic overgrowth conditions: A single-center experience. Mol Genet Genomic Med. 2019;7(3):e536.

57. Piacitelli A.M., Jensen D.M., Brandling-Bennett H., et al. Characterization of a severe case of PIK3CA-related overgrowth at autopsy by droplet digital polymerase chain reaction and report of PIK3CA sequencing in 22 patients. Am J Med Genet A. 2018;176(11):2301–2308.

58. Quinlan-Jones E., Williams D., Bell C., et al. Prenatal Detection of PIK3CA-related Overgrowth Spectrum in Cultured Amniocytes Using Long-range PCR and Next-generation Sequencing. Pediatr Dev Pathol. 2017;20(1):54–57.

59. Pirozzi F., Berkseth M., Shear R., et al. Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care. Brain. 2022 Apr 29;145(3):925–938.

60. Li D, Sheppard SE, March ME, et al. Genomic profiling informs diagnoses and treatment in vascular anomalies. Nat Med. 2023;29(6):1530–1539.

61. Zenner K., Jensen D.M., Cook T.T., et al. Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations. Genet Med. 2021;23(1):123–130.

62. Cossio M.-L., Rodríguez J., Flores J.C., et al. Four-month-old with severe PIK3CA-related overgrowth spectrum disorder successfully treated with alpelisb. Pediatr Dermatol. 2024;41(4):714–717.

63. Стенина М.Б., Жукова Л.Г., Королева И.А. и др. Практические рекомендации по лекарственному лечению рака молочной железы. Злокачественные опухоли. 2020;10(3s2-1):145-182.