Long-term survival of uveal melanoma patients after enucleation, depending on molecular genetic aberrations

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Abstract

Rationale: In the recent years molecular genetic prognostic factors are becoming very important for predicting the course of uveal melanoma (UM). In clinical practice, molecular genetic methods are used to identify patients with a high risk of metastases.

Aim: To determine the survival of UM patients after enucleation, depending on molecular genetic aberrations.

Materials and methods: Thirty (30) patients with UM aged from 23 to 83 years were examined and treated. In all cases, enucleation was performed. The removed eyes underwent morphological and molecular genetic and cytogenetic analysis (loss of heterozygocity on chromosomes 1, 3 and 8, methylation of the RASSF1A gene, mutations in GNAQ/11 genes, polymorphism of the ABCB1 gene). The median follow-up was 61 months.

Results: The cumulative 3-year survival of the UM patients was 77.8 ± 8.0%, and the 5-year survival 63.0 ± 9.0%. The mean survival time was 52.8 ± 3.9 months. The patients with chromosome 3 monosomy showed significantly lower 5-year survival rates than the patients with partial monosomy and without loss of heterozygocity in chromosome 3 (log-rank test, χ2 = 14.111, p = 0.001). The loss of heterozygocity on chromosomes 1 and 8, the methylation of the RASSF1A gene, the mutations in GNAQ/11 genes, and the polymorphism of the ABCB1 gene were not associated with poorer vital prognosis.

Conclusion: Molecular genetic aberrations play an important role in predicting the course of the tumor process and determining the risk of hematogenous metastasizing in UM patients. The significant role of chromosome 3 monosomy has been proved. Due to the relatively small cohort (30 patients) and the time factor (analysis of 5-year survival), the role of other molecular genetic changes has not been confirmed, which requires an assessment of not only genetic, but also clinical, echographic and morphological prognostic factors.

About the authors

V. V. Neroev

Moscow Helmholtz Research Institute of Eye Diseases

Email: fake@neicon.ru

Vladimir V. Neroev – MD, PhD, Professor, Member-Correspondent of Russian Academy of Sciences, Director 

14/19 Sadovaya-Chernogryazskaya ul., Moscow, 105062

Россия

S. V. Saakyan

Moscow Helmholtz Research Institute of Eye Diseases

Email: fake@neicon.ru

Svetlana V. Saakyan – MD, PhD, Professor, Head of Department of Ophthalmic Oncology and Radiology 

14/19 Sadovaya-Chernogryazskaya ul., Moscow, 105062

Россия

A. G. Amiryan

Moscow Helmholtz Research Institute of Eye Diseases

Author for correspondence.
Email: amiryan@yandex.ru

Anush G. Amiryan – MD, PhD, Leading Research Fellow, Department of Ophthalmic Oncology and Radiology 

14/19 Sadovaya-Chernogryazskaya ul., Moscow, 105062

Россия

A. Yu. Tsygankov

Moscow Helmholtz Research Institute of Eye Diseases

Email: fake@neicon.ru

Alexander Yu. Tsygankov – MD, PhD, Junior Research Fellow, Department of Ophthalmic Oncology and Radiology 

14/19 Sadovaya-Chernogryazskaya ul., Moscow, 105062

Россия

A. M. Burdennyy

Institute of General Pathology and Pathophysiology

Email: fake@neicon.ru

Alexey M. Burdennyy – PhD (in Biology), Senior Research Fellow, Laboratory of Pathogenomics and Transcriptomics 

8 Baltiyskaya ul., Moscow, 125315

Россия

V. I. Loginov

Institute of General Pathology and Pathophysiology

Email: fake@neicon.ru

Vitaly I. Loginov – PhD (in Biology), Leading Research Fellow, Laboratory of Pathogenomics and Transcriptomics 

8 Baltiyskaya ul., Moscow, 125315

Россия

M. R. Khlgatyan

Moscow Helmholtz Research Institute of Eye Diseases

Email: fake@neicon.ru

Mariam R. Khlgatyan – MD, Opthalmologist, Postgraduate Student, Department of Ophthalmic Oncology and Radiology

14/19 Sadovaya-Chernogryazskaya ul., Moscow, 105062

Россия

References

  1. Coupland SE, Lake SL, Zeschnigk M, Damato BE. Molecular pathology of uveal melanoma. Eye (Lond). 2013;27(2): 230–42. doi: 10.1038/eye.2012.255.
  2. Caines R, Eleuteri A, Kalirai H, Fisher AC, Heimann H, Damato BE, Coupland SE, Taktak AF. Cluster analysis of multiplex ligation-dependent probe amplification data in choroidal melanoma. Mol Vis. 2015;21:1–11.
  3. Damato BE, Heimann H, Kalirai H, Coupland SE. Age, survival predictors, and metastatic death in patients with choroidal melanoma: tentative evidence of a therapeutic effect on survival. JAMA Ophthalmol. 2014;132(5): 605–13. doi: 10.1001/jamaophthalmol.2014.77.
  4. Woodman SE. Metastatic uveal melanoma: biology and emerging treatments. Cancer J. 2012;18(2): 148–52. doi: 10.1097/PPO.0b013e31824bd256.
  5. Саакян СВ, Цыганков АЮ, Амирян АГ, Логинов ВИ, Бурденный АМ. Потеря гетерозиготности на хромосомах 1, 3, 8 при увеальной меланоме. Молекулярная медицина. 2018;16(2): 37–40. doi: 10.29296/249994902018-02-05.
  6. Isager P, Ehlers N, Overgaard J. Prognostic factors for survival after enucleation for choroidal and ciliary body melanomas. Acta Ophthalmol Scand. 2004;82(5): 517–25. doi: 10.1111/j.1600-0420.2004.00330.x.
  7. Triozzi PL, Eng C, Singh AD. Targeted therapy for uveal melanoma. Cancer Treat Rev. 2008;34(3): 247–58. doi: 10.1016/j.ctrv.2007.12.002.
  8. Саакян СВ, Амирян АГ, Цыганков АЮ, Логинов ВИ, Бурденный АМ. Мутации в онкогенах GNAQ и GNA11 у больных увеальной меланомой. Молекулярная медицина. 2014;(2): 34–7.
  9. Саакян СВ, Амирян АГ, Цыганков АЮ, Логинов ВИ, Бурденный АМ. Ассоциация гена ABCB1 с риском развития увеальной меланомы. Архив патологии. 2014;76(2): 3–7.
  10. Саакян СВ, Цыганков АЮ, Амирян АГ, Логинов ВИ, Бурденный АМ. Анализ статуса метилирования CPG-островков генов-супрессоров опухолевого роста RASSF1A и SEMA3B при увеальной меланоме. Молекулярная медицина. 2018;16(1): 51–4. doi: 10.29296/24999490-2018-01-09.
  11. Coupland SE, Kalirai H, Ho V, Thornton S, Damato BE, Heimann H. Concordant chromosome 3 results in paired choroidal melanoma biopsies and subsequent tumour resection specimens. Br J Ophthalmol. 2015;99(10): 1444–50. doi: 10.1136/bjophthalmol2015-307057.
  12. Damato B, Eleuteri A, Taktak AF, Coupland SE. Estimating prognosis for survival after treatment of choroidal melanoma. Prog Retin Eye Res. 2011;30(5): 285–95. doi: 10.1016/j.preteyeres.2011.05.003.
  13. Bronkhorst IH, Maat W, Jordanova ES, Kroes WG, Schalij-Delfos NE, Luyten GP, Jager MJ. Effect of heterogeneous distribution of monosomy 3 on prognosis in uveal melanoma. Arch Pathol Lab Med. 2011;135(8): 1042–7. doi: 10.5858/2010-0477-OAR1.
  14. Dogrusoz M, Bagger M, van Duinen SG, Kroes WG, Ruivenkamp CA, Bohringer S, Andersen KK, Luyten GP, Kiilgaard JF, Jager MJ. The prognostic value of AJCC staging in uveal melanoma is enhanced by adding chromosome 3 and 8q status. Invest Ophthalmol Vis Sci. 2017;58(2): 833–42. doi: 10.1167/iovs.1620212.
  15. Shields CL, Say EAT, Hasanreisoglu M, Saktanasate J, Lawson BM, Landy JE, Badami AU, Sivalingam MD, Hauschild AJ, House RJ, Daitch ZE, Mashayekhi A, Shields JA, Ganguly A. 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.
  16. Maat W, van der Velden PA, Out-Luiting C, Plug M, Dirks-Mulder A, Jager MJ, Gruis NA. Epigenetic inactivation of RASSF1A in uveal melanoma. Invest Ophthalmol Vis Sci. 2007;48(2): 486–90. doi: 10.1167/iovs.06-0781.
  17. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O'Brien J, Bastian BC. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23): 2191–9. doi: 10.1056/NEJMoa1000584.
  18. Decatur CL, Ong E, Garg N, Anbunathan H, Bowcock AM, Field MG, Harbour JW. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 2016;134(7): 728– 33. doi: 10.1001/jamaophthalmol.2016.0903.
  19. Mudhar HS, Doherty R, Salawu A, Sisley K, Rennie IG. Immunohistochemical and molecular pathology of ocular uveal melanocytoma: evidence for somatic GNAQ mutations. Br J Ophthalmol. 2013;97(7): 924–8. doi: 10.1136/ bjophthalmol-2013-303291.
  20. Vader MJC, Madigan MC, Versluis M, Suleiman HM, Gezgin G, Gruis NA, Out-Luiting JJ, Bergman W, Verdijk RM, Jager MJ, van der Velden PA. 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.

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Copyright (c) 2018 Neroev V.V., Saakyan S.V., Amiryan A.G., Tsygankov A.Y., Burdennyy A.M., Loginov V.I., Khlgatyan M.R.

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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