LOSS OF HETEROZYGOSITY ON CHROMOSOMES 1, 3 AND 8 IN UVEAL MELANOMA PATIENTS

DOI: https://doi.org/10.29296/24999490-2018-02-05

S.V. Saakyan(1, 2), A.Iu. Tsygankov(1, 2), A.G. Amiryan(1), V.I. Loginov(3), A.M. Burdennyy(3) 1-Helmholtz Moscow Research Institute of Eye Diseases, Sadovaya-Chernogryazskaya str. 14/19, Moscow, 105062, Russian Federation; 2-A.I. Evdokimov Moscow State University of Medicine and Dentistry, Delegatskaya str., 20/1, Moscow, 127473, Russian Federation; 3Research Institute of General Pathology and Pathophysiology, Baltiiskaya str., 8, Moscow, 125315, Russian Federation E-mail: [email protected]

Introduction. Uveal melanoma (UM) is the most common primary intraocular tumor in adults. This type of cancer is characterized by the high metastatic activity in the liver, which is the crucial factor for 95% of patients’ bad outcome in any case of the treatment method. The crucial role of loss of heterozygosity (LOH) on chromosomes 1, 3 and 8 in the genome instability and the development of the metastatic activity is shown, where the monosomy of chromosome 3 is the most important. The aim of the study. The aim of the present paper was the study of LOH on chromosomes 1,3 and 8 in UM and their correlation with clinical and morphological characteristics of the tumor. Methods. The analysis of allelic deletions in chromosomes 1, 3 and 8 were carried out in 38 samples obtained from patients residing in Central Russia region. All tumors were histologically verified. Results. According to data of the analysis of LOH on chromosome 3 we revealed full monosomy in 8 cases out of 38 (21%). Furthermore, we have shown LOH to be also detected in at least one of the 11 loci of studied chromosome 3 in 57.9% (22/38) of cases, including in fragile histidine triad protein (FHIT) (D3S4103-D3S1481, 3p14.2) in 5 cases of 22 (22,7%). The prevalence rate of LOH at the locus 1p36.22 accounted of 28.9% (11/38), at loci 8p12-p22 – 21% (8/38). In 9 of the 11 cases with LOH in locus 1p36.21-22 we observed LOH also on chromosome 3 (p=0,03). Also, all the cases of LOH on chromosome 8 are accompanied by allelic loss on chromosome 3 (p=0,018). Conclusion. We studied the frequency of allelic deletions in chromosomes 1, 3 and 8 in UM samples. The critical role of aberrations of studied chromosomes in UM is shown.
Keywords: 
uveal melanoma, deletions, loss of heterozygosity, monosomy of chromosome 3
Список литературы: 
  1. Brovkina A.F. Sovremennye aspekty lecheniya melanom horioidei: problemy, diskussionnye voprosy. Vestnik oftal`mologii. 2006; 122 (1): 13–5. [Brovkina A.F. Current aspects of treatment for choroidal melanomas: problems, controversial questions. Annals of ophthalmology. 2006; 122 (1): 13–5 (In Russian)]
  2. Shields C.L. The hunt for the secrets of uveal melanoma. Clin Experiment Ophthalmol. 2008; 36 (3): 277–80.
  3. Thomas S., Pütter C., Weber S., Bornfeld N., Lohmann D.R., Zeschnigk M. Prognostic significance of chromosome 3 alterations determined by microsatellite analysis in uveal melanoma: a long-term follow-up study. Br. J. Cancer. 2012; 106 (6): 1171–6.
  4. Saakyan S.V., Cygankov A.Yu., Amiryan A.G., Sklyarova N.V., Zaletaev D.V. Vyzhivaemost` pri uveal`noy melanome: rol` molekulyarno-geneticheskih faktorov. Vestnik oftal`mologii. 2016; 132(1): 3–9. [Saakyan S.V., Tsygankov A.Yu., Amiryan A.G., Sklyarova N.V., Zaletaev D.V. Role of molecular and genetic changes in survival from uveal melanoma. Annals of ophthalmology. 2016; 132(1): 3–9. (in Russian)]
  5. Van den Bosch T., Kilic E., Paridaens D., de Klein A. Genetics of uveal melanoma and cutaneous melanoma: two of a kind? Dermatol Res Pract. 2010; 2010:360136.
  6. Manohina I.K., Zemlyakova V.V., Sklyarova N.V., Saakyan S.V., Zaletaev D.V. Sravnitel`nyy analiz molekulyarnyh narusheniy v patogeneze uveal`noy melanomy i melanomy kozhi. Rossiyskiy oftal`mologicheskiy zhurnal. 2010; 2: 13–5. [Manokhina I.K., Zemlyakova V.V., Skljarova N.V., Saakyan S.V., Zaletaev D.V. A comparative analysis of molecular disorders in the pathogenesis of uvea and skin . Russian ophthalmological journal. 2010; 2: 13–5 (in Russian)]
  7. Kilic E., Naus N.C., van Gils W., Klaver C.C., van Til M.E., Verbiest M.M., Stijnen T., Mooy C.M., Paridaens D., Beverloo H.B., Luyten G.P., de Klein A. Concurrent loss of chromosome arm 1p and chromosome3 predicts a decreased disease free survival in uveal melanoma patients. Invest Ophthalmol Vis Sci. 2005; 46: 2253–7.
  8. Manohina I.K., Sklyarova N.V., Saakyan S.V., Zaletaev D.V. Analiz allel`nyh poter` v uveal`nyh melanomah. Medicinskaya genetika. 2008; 7 (6): 19–23. [Manokhina I.K., Sklyarova N.V., Saakyan S.V., Zaletaev D.V. Analysis of allelic loss in uveal melanoma. Medical genetics. 2008; 7 (6): 19–23 (in Russian)]
  9. Minca E.C., Tubbs R.R., Portier B.P., Wang Z., Lanigan C., Aronow M.E., Triozzi P.L., Singh A., Cook J.R., Saunthararajah Y., Plesec T.P., Schoenfield L., Cawich V., Sulpizio S., Schultz R.A. Genomic microarray analysis on formalin-fixed paraffin-embedded material for uveal melanoma prognostication Cancer Genet. 2014; 207 (7–8): 306–15.
  10. Van Gils W., Kilic E., Brüggenwirth H.T., Vaarwater J., Verbiest M.M., Beverloo B., van Til-Berg M.E., Paridaens D., Luyten G.P., de Klein A. Regional deletion and amplification on chromosome 6 in a uveal melanoma case without abnormalities on chromosome 1p,3 and 8. Melanoma Res. 2008; 18: 10–5.
  11. Abdel-Rahman M.H., Christopher B.N., Faramawi M.F., Said-Ahmed K., Cole C., McFaddin A., Ray-Chaudhury A., Heerema N., Davidorf F.H. Frequency, molecular pathology and potential clinical significance of partial chromosome 3 aberrations in uveal melanoma. Mod Pathol. 2011; 24: 954–62.
  12. Shields C.L., Ganguly A., Bianciotto C.G., Turaka K., Tavallali A., Shields J.A. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology.2011; 118: 396–401.
  13. Radhakrishnan A., Badhrinarayanan N., Biswas J., Krishnakumar S. Analysis of chromosomal aberration (1, 3, and 8) and association of microRNAs in uveal melanoma. Mol Vis. 2009; 15: 2146–54.
  14. Schoenfield L., Pettay J., Tubbs R.R., Singh A.D. Variation of monosomy 3 status within uveal melanoma. Arch Pathol Lab Med. 2009; 133 (8): 1219–22.
  15. Rishi P., Koundanya V.V., Shields C. Using risk factors for detection and prognostication of uveal melanoma. Indian J. Ophthalmol. 2015; 63: 110–6.