Association of clinical, instrumental and molecular genetic predictors with the risk of development and tumor progression of melanocytic intraocular neoplasms

Purpose: to analyze the frequency and possible associations of GNAQ and GNA11 oncogenes in peripheral blood ctDNA, as well as the relationship of the ABCB1/MDR1 rs1045642 polymorphic marker gene with the clinical and instrumental characteristics of nevi and initial choroidal melanoma. Material and methods. A prospective study of 81 previously untreated patients (84 eyes, mean age 57.8 ± 13.8 years) included general ophthalmological examinations and special instrumental diagnostics: ultrasound checkups, spectral optical coherent tomography (SOCT), OCT angiography. Depending on the nature of the pathology, the patients were divided into three groups: I — with benign choroidal nevus (23 eyes, 28 %; mean age 61.1 ± 13.6 years); II — with suspicious choroidal nevus (24 eyes, 29 %; mean age 54.8 ± 13.0 years); III — small choroidal melanoma (37 eyes, 43 %; mean age 56.2 ± 14.8 years). Genotyping was performed by melting curve analysis. Results. A significant association was revealed between the presence of ctDNA (GNAQ/GNA11 oncogenes) and the CC genotype of the ABCB1 gene with the risk of developing a small melanoma of the choroid and choroidal nevi. In patients with suspicious choroidal nevus, there is an unfavorable significance of mutations in the GNAQ/GNA11 genes (ctDNA). A relative unfavorable predictive significance of the presence of mutations in the GNAQ/GNA11 genes in peripheral blood ctDNA of patients with a benign choroidal nevus was suggested. No significant associations between GNAQ/GNA11 mutations, ABCB1 gene polymorphism and clinical/instrumental tumor features were found. Conclusion. The revealed features can be used for screening the patients with melanocytic intraocular tumors and for developing modern approaches to predicting the course of UM in the early preclinical period.

melanocytic intraocular tumors, GNAQ/GNA11 oncogenes, MDR1/АBСB1 gene

1. Brovkina A.F. Ophthalmooncology. A guide for physicians. Moscow: Meditsina; 2002 (in Russian).

2. Myakoshina E.B. Small choroidal melanoma and pseudomelanomas: methods of differential diagnostics. Part 1. Ophthalmoscopy. Russian ophthalmological journal. 2019; 12 (4): 99–108 (In Russian). doi: 10.21516/2072-0076-2019-12-4-99-108

3. Shields C.L., Dalvin L.A., Ancona-Lezama D., et al. Choroidal nevus imaging features in 3806 cases and risk factors transformation into melanoma in 2355: The 2020 Taylor R. Smith and Victor T. Curtin Lecture. Retina. 2019; 39 (10): 1840–51. doi: 10.1097/IAE.0000000000002440

4. Vader M.J.C., Madigan M.C., Versluis M., et al. GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi. Br. Journ. of Cancer. 2017; 117 (6): 884–7. doi:10.1038/bjc.2017.259

5. Harbour J.W., Paez-Escamilla M., Cai L., et al. Are risk factors for growth of choroidal nevi associated with malignant transformation? Assessment with a validated genomic biomarker. Am. Journ. of Ophthalmology. 2019; 197: 168–79. doi:10.1016/j.ajo.2018.08.045

6. Saakyan S.V., Amiryan A.G., Tsygankov A.Yu., et al. Association of the ABCB1 gene with risk for uveal melanoma. Arkhiv patologii. 2014; 76 (2): 3–7 (in Russian).

7. Landreville S., Agapova O.A., Kneass Z.T., et al. ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity. Pigment Cell and Melanoma Research. 2011; 24 (3): 430–7. doi: 10.1111/j.1755148X.2011.00841.x

8. Saakyan S.V., Khlgatyan M.R., Tsygankov A.Yu., et al. The role of the C3435T polymorphic marker of the ABCB1 gene in the development of early choroidal melanoma. Russian ophthalmological journal. 2020; 13 (1): 51–8 (In Russian). doi: 10.21516/20720076-2020-13-1-51-58

9. Aaron N., Colin A.M., Christian M., et al. Vitrectomy-assisted biopsy for molecular prognostication of choroidal melanoma. Retina. 2017; 37 (7): 1377–82. doi: 10.1097/IAE.0000000000001362

10. Telysheva E.N. Cell-free circulating DNA in plasma. Possibility of application in oncology. Vestnik of the Russian Scientific Center of Roentgenoradiology of the Ministry of Healthcare of the Russian Federation. 2017; 2: 1–29 (in Russian).

11. Bidard F.C., Madic J., Mariani P., et al. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. International journal of cancer. 2014; 134 (5): 1207–13. doi:10.1002/ijc.28436

12. Bryan C.U., Cloud P.P. Cell-Free DNA in oncology: gearing up for clinic. Annals of Laboratory Medicine. 2018; 38 (1): 1–8. doi: 10.3343/alm.2018.38.1.1

13. Alexander N.S., Richard D.C. GNAQ and GNA11 mutations in uveal melanoma. Melanoma Research. 2014; 24 (6): 525–34. doi: 10.1097/CMR.0000000000000121

14. Saakyan S.V., Amiryan A.G., Tsygankov A.Yu., et al. Mutations in oncogenes GNAQ and GNA11 in uveal melanoma patients. Molecular Medicine. 2014; 2: 34–7 (in Russian).

15. Zavarykina Т.М., Tyulyandina А.S., Loginov V.I., et al. Association of polymorphic markers of XRCC1, ERCC2, CDKN1A genes with progression free survival of ovarian cancer patients after platinum/taxanes-based chemotherapy. Patogenez. 2019; 17 (1): 72–81 (in Russian). doi: 10.25557/2310-0435.2019.01.72-81

16. Saakyan S.V., Tsygankov A.Yu., Amiryan A.G., et al. Molecular factors of tumor progression in uveal melanoma. Effective pharmacotherapy. 2016; 39: 46–51 (in Russian).

17. Myakoshina E.B., Saakyan S.V. Optical coherence tomography in diagnostics of small choroidal melanoma. Vestnik oftal’mologii. 2020; 136 (1): 56–64 (in Russian). doi:10.17116/oftalma202013601156

18. Garcia-Arumi Fuste C., Peralta Iturburu F., Garcia-Arumi J. Is optical coherence tomography angiography helpful in the differential diagnosis of choroidal nevus versus melanoma? European Journal of Ophthalmology. 2020; 30 (4): 723–9. doi: 10.1177/1120672119851768

19. Frizziero L., Midena E., Trainiti S., et al. Uveal melanoma biopsy: a review. Cancers (Basel). 2019; 11 (8): 1075. doi: 10.3390/cancers11081075

20. Madic J., Piperno-Neumann S., Servois V., et al. Pyrophosphorolysis-activated polymerization detects circulating tumor DNA in metastatic uveal melanoma. Clinical Cancer Research. 2012; 18 (14): 3934–41. doi: 10.1158/1078-0432.CCR-12-0309

21. Bande R.M.F., Fernandez M.B, Lago B.N., et al. Blood biomarkers of uveal melanoma: current perspectives. Clinical Ophthalmology. 2020; 14: 157–69. doi: 10.2147/OPTH.S199064

22. Metz Hd. C., Scheulen M., Bornfeld N., et al. Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma. Cancer Medicine. 2013; 2 (2): 208–15. doi: 10.1002/cam4.61

23. Cabel L., Riva F., Servois V. Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study. Annals of Oncology. 2017; 28 (8): 1996–2001. doi: 10.1093/annonc/mdx212

24. Tsygankov A.Yu., Saakyan S.V., Amiryan A.G. A role of clinical, pathomorphology and genetic factors in survival of patients with uveal melanoma. Effective pharmacotherapy. 2016; 39: 52–9 (in Russian).

25. Diehl F., Schmidt K., Choti A.M., et al. Circulating mutant DNA to assess tumor dynamics. Nature Medicine. 2008; 14 (9): 985–90. doi: 10.1038/nm.1789