Minimally invasive differential diagnosis of melanocytic intraocular neoplasms

Purpose: to analyze the mutation frequency of the GNAQ/GNA11 gene in circulating tumor DNA and genotypes of the polymorphic marker C3435T of the ABCB1 gene in a large sample of patients with intraocular melanocytic neoplasms (IMN).

Material and methods. In an open prospective study performed in 2015–2022, 272 IMN patients with intraocular melanocytic neoplasms aged 28 to 87 (ave. 58.3 ± 12.6), including 187 females (68.8 %) and 85 males (31.2 %), were divided into three groups depending on the nature of the tumor focus: Group I, n = 141, progressing choroidal melanomas; Group II, n = 67, stationary melanomas, and Group III, n = 64, choroidal nevi.

Results. In Group I, at least one mutation in the GNAQ/GNA11 gene was detected in 134 patients (95.0 %). Of these, 35 patients (24.8 %) revealed two mutations, and 16 patients (11.3 %) had 3 mutations. In Group II, one mutation was detected in 49 patients (73.1 %), of which three patients (4.5 %) had two mutations. In Group III, one mutation in the GNAQ/GNA11 gene was detected in 13 patients (20.3 %). When comparing the overall frequency of mutations in the GNAQ/GNA11 genes in Groups I and II, significant differences were obtained (OR = 7.03 (2.77 to 17.86), F = 0.000015, ξ2 = 20.6), with Group I having mutations identified in 95 % of cases and Group II, in 73.1 %. Significant differences were also obtained when comparing the frequency of the studied mutations in Groups I and III (OR = 75.1 (28.36 to 198.86), F = 0.0000001, ξ2 = 121.15) with a frequency of 20.3 % in Group III. The frequency of mutations in the GNAQ/GNA11 genes was significantly higher in Group II than in Group III (OR = 10.68 (4.73 to 24.1), F = 0.0000001, ξ2 = 36.64). The frequencies of heterozygous mutations in all 4 exons were significantly higher in Group I than in Groups II and III, except for the GNAQ183 gene when comparing Groups I and II. Heterozygous mutations in all 4 exons were significantly more frequent in Group II than in Group III. Homozygous mutations were found only in Group I patients, but, in spite of this, no significant differences were detected when comparing them with other groups. The frequency of genotype CC of the polymorphic marker C3435T of ABCB1 gene was significantly lower in Group I as compared to Group II, whilst the frequency of genotype CT was significantly higher than in group II.

Conclusion. The general analysis of molecular genetic studies of 272 patients with intraocular melanocytic neoplasms showed a direct correlation between the frequency of detection of mutations in genes and the size and source of the tumor. The obtained results substantiate both screening of patients from risk groups and differentiation of patients depending on the size and source of the tumor.

1. Kalirai H, Tsygankov AI, Thornton S, Saakyan SV, Coupland SE. Genetics of uveal melanoma. In: Khetan V, ed. Intraocular Tumors. Springer, Singapore; 2020. doi:10.1007/978-981-15-0395-5_7

2. Smit KN, Jager MJ, de Klein A, Kili E. Uveal melanoma: towards a molecular understanding. Prog Retin Eye Res. 2020; 75: 100800. doi: 10.1016/j.preteyeres.2019.100800

3. Bustamante P, Piquet L, Landreville S, Burnier JV. Uveal melanoma pathobiology: metastasis to the liver. Semin Cancer Biol. 2021; 71: 65–85. doi: 10.1016/j.semcancer.2020.05.003

4. Amaro A, Gangemi R, Piaggio F, et al. The biology of uveal melanoma. Cancer Metastasis Rev. 2017; 36 (1): 109–140. doi: 10.1007/s10555-017-9663-3

5. Hammer H, Oláh J, Tóth-Molnár E. Dysplastic nevi are a risk factor for uveal melanoma. Eur J Ophthalmol. 1996; 6 (4): 472–4. doi:10.1177/112067219600600423

6. Shields CL, Kaliki S, Livesey M, et al. Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872 consecutive eyes. JAMA Ophthalmol. 2013; 131 (8): 993–1003. doi:10.1001/jamaophthalmol.2013.129

7. Abdel-Rahman MH, Pilarski R, Cebulla CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011; 48 (12): 856–9. doi: 10.1136/jmedgenet-2011-100156

8. Saakyan S.V., Amiryan A.G., Tsygankov A.Iu., Loginov V.I., Burdennyy A.M. Mutations in oncogenes GNAQ and GNA11 in uveal melanoma patients. Molecular medicine. 2014; 2: 34–7 (in Russ.).

9. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010; 363 (23): 2191–9. doi:10.1056/NEJMoa1000584

10. Nayman T, Bostan C, Logan P, Burnier MN, Jr. Uveal melanoma risk factors: a systematic review of meta-analyses. Curr Eye Res. 2017; 42 (8): 1085–93. doi: 10.1080/02713683.2017.1297997

11. Moore AR, Ceraudo E, Sher JJ, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet. 2016; 48 (6): 675–80. doi:10.1038/ng.3549

12. Johansson P, Aoude LG, Wadt K, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2016; 7 (4): 4624–31. doi:10.18632/oncotarget.6614

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

14. Saakyan S.V., Tsygankov A.Yu., Myakoshina E.B., et al. Association of clinical, instrumental and molecular genetic predictors with the risk of development and tumor progression of melanocytic intraocular neoplasms. Russian ophthalmological journal. 2020; 13 (4): 24–32 (In Russ.). doi:10.21516/2072-0076-2020-13-4-24-32

15. Marous CL, Shields CL, Yu MD, et al. Malignant transformation of choroidal nevus according to race in 3334 consecutive patients. Indian J Ophthalmol. 2019; 67 (12): 2035–42. doi: 10.4103/ijo.IJO_1217_19

16. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 2009; 127 (8): 989–98. doi: 10.1001/archophthalmol.2009.208

17. Frizziero L, Midena E, Trainiti S, et al. Uveal melanoma biopsy: A review. Cancers (Basel). 2019 Jul 30; 11 (8): 1075. doi: 10.3390/cancers11081075

18. Mccannel T. Choroidal melanoma: updates for a challenging disease. Retin Physician. 2014; 12: 35–7. https://www.retinalphysician.com/issues/2014/ march-2014/choroidal-melanoma-updates-for-a-challenging-dise

19. Augsburger JJ, Correa ZM, Trichopoulos N, Shaikh A. Size overlap between benign melanocytic Choroidal nevi and Choroidal malignant melanomas. Invest Ophthalmol Vis Sci. 2008; 49 (7): 2823–8. doi: 10.1167/iovs.07-1603

20. Shields CL, Say EAT, Hasanreisoglu M, et al. Personalized prognosis of Uveal melanoma based on cytogenetic profile in 1059 patients over an 8-year period: the 2017 Harry S. Gradle Lecture. Ophthalmology. 2017; 124 (10): 1523–31. doi:10.1016/j.ophtha.2017.04.003

21. Pantel K., Alix-Panabieres C. Liquid biopsy and minimal residual disease — latest advances and implications for cure. Nat Rev Clin Oncol. 2019; 16 (7): 409–24. doi: 10.1038/s41571-019-0187-3

22. Bande Rodriguez MF, Fernandez Marta B, Lago Baameiro N, et al. Blood biomarkers of uveal melanoma: current perspectives. Clin Ophthalmol. 2020; 14: 157–69. doi:10.2147/OPTH.S199064

23. Yu H, Han L, Yuan J, Sun Y. Circulating tumor cell free DNA from plasma and urine in the clinical management of colorectal cancer. Cancer Biomark. 2020; 27 (1): 29–37. doi:10.3233/CBM-182344

24. Wang Y, Springer S, Mulvey CL, et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015; 7 (293): 293ra104. doi:10.1126/scitranslmed.aaa8507

25. Zhang P, Wu X, Tang M, Nie X, Li L. Detection of EGFR gene mutation status from pleural effusions and other body fluid specimens in patients with lung adenocarcinoma. Thorac Cancer. 2019; 10 (12): 2218–24. doi: 10.1111/1759-7714.13201

26. Jin E, Burnier JV. Liquid biopsy in Uveal melanoma: are we there yet? Ocular Oncol Pathol. 2021; 7 (1): 1–16. doi: 10.1159/000508613

27. Saakyan S.V., Khlgatyan M.R., Tsygankov A.Yu., et al. OCT-morphometric and genetic predictors of the malignant transformation in melanocytic intraocular tumor. Head and neck. Russian journal. 2020; 8 (4): 8–16 (In Russ.). doi: 10.25792/HN.2020.8.4.8–16

28. Saakyan S.V., Khlgatyan M.R., Tsygankov A.Yu., Burdennyi A.M., Loginov V.I. 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 Russ.). doi:10.21516/2072-0076-2020-13-1-51-58

29. Heitzer E, Auinger L, Speicher MR. Cell-free DNA and apoptosis: how dead cells inform about the living. Trends Mol Med. 2020; 26 (5): 519–28. doi: 10.1016/j.molmed.2020.01.012

30. Siravegna G, Mussolin B, Venesio T, et al. How liquid biopsies can change clinical practice in oncology. Ann Oncol. 2019; 30 (10): 1580–90. doi: 10.1093/annonc/mdz227

31. Busser B, Lupo J, Sancey L, et al. Plasma circulating tumor DNA levels for the monitoring of melanoma patients: landscape of available technologies and clinical applications. Biomed Res Int. 2017; 2017: 5986129. doi:10.1155/2017/5986129

32. Bustamante P, Tsering T, Coblentz J, et al. Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma. J Exp Clin Cancer Res. 2021; 40 (1): 196. doi: 10.1186/s13046-021-01984-w.оа

33. 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 Russ.).