|Generate QR code
Open Access
Subscription Access
PIK3CA-related overgrowth spectrum: molecular mechanism, diagnostic and therapy features
https://doi.org/10.25557/2073-7998.2024.12.3-15
Abstract
Postzygotic somatic variants in cancer-associated genes underlie a range of overgrowth and vascular malformations syndromes. PIK3CA-related overgrowth spectrum (PROS) is one of the key diseases in this group, which encompasses more than 20 conditions marked by asymmetric overgrowth and vascular malformations. The PIK3CA gene encodes the catalytic subunit p110α of phosphatidylinositol- 3-kinase and is mutated in various types of cancer. The mutational events in PROS occur during embryonic development, resulting in a mosaic distribution of mutations. The diversity and severity of PROS clinical manifestations are determined by a combination of factors, including the degree of PI3K activation by specific variants, the type of affected tissue, the timing of mutation occurrence, and the influence of additional factors. The high phenotypic variability of PROS, its similarity to other overgrowth vascular syndromes, as well as the challenges of molecular genetic diagnosis of mosaic variants, complicate the diagnosis of PROS. In this work, we summarize the current knowledge about the molecular mechanisms of PROS, the involvement of the regulatory subunit in the pathogenesis of PROS, and discuss the diagnostic and therapeutic features of this condition.
Supporting agencies: The study was carried out according to the state assignment of the Ministry of Science and Higher Education of the Russian Federation for the Research Centre for Medical Genetics.
About the Authors
E. V. Bychkova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
Ekaterina V. Bychkova
1, Moskvorechie st., Moscow, 115522
N. A. Semenova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
G. B. Sagoyan
National Medical Research Center of Oncology named after N.N. Blokhin of the Ministry of Health of the Russian Federation
Russian Federation
Russian Federation
23, Kashirskoe shosse, Moscow, 115522
D. M. Guseva
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
V. V. Strelnikov
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
References
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. Stenina M.B., Zhukova L.G., Koroleva I.A. et al. Prakticheskiye rekomendatsii po lekarstvennomu lecheniyu raka molochnoy zhelezy [Practical recommendations for drug treatment of breast cancer]. Zlokachestvennyye opukholi [Malignant tumors]. 2020;10(3s2-1):145-182. (In Russ.)
Review
For citations:
Bychkova E.V., Semenova N.A., Sagoyan G.B., Guseva D.M., Strelnikov V.V. PIK3CA-related overgrowth spectrum: molecular mechanism, diagnostic and therapy features. Medical Genetics. 2024;23(12):3-15. (In Russ.) https://doi.org/10.25557/2073-7998.2024.12.3-15
Views:
204
Email this article 