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Prognostic impact of HERC2 protein and pink-eyed dilution protein in uveal melanoma

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Abstract

Biological understanding of pigmentation and its association with clinicopathological implications in uveal melanoma (UM) risk is still unexplored. HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2 (HERC2) and Pink-eyed dilution protein (P-protein) are the important markers that regulate pigmentation in eye. Therefore, our aim of the study was to investigate the expression of HERC2 and P-protein in the UM patients and correlate with patient outcome. Fifty-two formalin-fixed paraffin-embedded UM tissue samples were included to detect the expression of HERC2 and P-protein by immunohistochemistry and validated by western blot. Cox proportional hazard model and log-rank test were used to determine the prognostic potential of these proteins. High pigmentation was seen in 67% of the UM cases. The expression of HERC2 and P-protein was present in 44% and 71% cases, respectively. On statistical analysis, increased pigmentation, epithelioid cell type, and ciliary body invasion were significant with the protein expressions (p < 0.05). Metastasis-free survival was reduced in UM cases which expressed HERC2 and P-protein. On multivariate analysis, P-protein expression was found to be an independent prognostic factor. Our findings suggest that HERC2 and P-protein could be used as novel predictors of high pigmentation in UM cases which have high metastatic potential.

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References

  1. Manni S, Durairaj P, Yeung J. Uveal melanoma: a review of the literature. Oncol Ther. 2018;6:87–104.

    Article  Google Scholar 

  2. Francis JH, Shoushtari AN, Barker CA, Abramson DH. Uveal melanoma: diagnosis, prognosis and current treatments for primary and metastatic disease. Melanoma Lett. 2016;34:3.

    Google Scholar 

  3. Hu DN, Yu GP, McCormick SA, Schneider S, Finger PT. Population-based incidence of uveal melanoma in various races and ethnic groups. Am J Ophthalmol. 2005;140:612–7.

    Article  Google Scholar 

  4. Harbour JW, Brantley MA, Hollingsworth H, Gordon M. Association between choroidal pigmentation and posterior uveal melanoma in a white population. Br J Ophthalmol. 2004;88:39–433.

    Article  CAS  Google Scholar 

  5. Brożyna AA, Jozwicki W, Roszkowski K, Filipiak J, Slominsk AT. Melanin content in melanoma metastases affects the outcome of radiotherapy. Oncotarget. 2016;7:17844–53.

    Article  Google Scholar 

  6. Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev. 2004;84:1155–228.

    Article  CAS  Google Scholar 

  7. Mochizuki M, Sugita S, Kamoi K. Immunological homeostasis of the eye. Progress Retinal Eye Res. 2013;33:10–27.

    Article  CAS  Google Scholar 

  8. Bronkhorst IH, Jager MJ. Inflammation in uveal melanoma. Eye. 2013;27:217–23.

    Article  CAS  Google Scholar 

  9. COMS report no. 6. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. Am J Ophthalmol. 1998;125:745–66.

    Article  Google Scholar 

  10. Box NF, Chen W, Sturm RA, et al. Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Investig Dermatol. 2001;116:224–9.

    Article  CAS  Google Scholar 

  11. Rishi P, Koundanya V, Shields CL. Using risk factors for detection and prognostication of uveal melanoma. Indian J Ophthalmol. 2015;63:110–6.

    Article  Google Scholar 

  12. Kayser M, Liu F, Janssens AC, Rivadeneira F, Lao O, van Duijn K, Vermeulen M, Arp P, Jhamai MM, van IJcken WF, den Dunnen JT. Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. Am J Hum Genet. 2008;8(82):411–23.

    Article  Google Scholar 

  13. Brilliant MH. The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res. 2001;14:86–93.

    Article  CAS  Google Scholar 

  14. Eiberg H, Troelsen J, Nielsen M, et al. Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Hum Genet. 2008;123:177–87.

    Article  CAS  Google Scholar 

  15. Visser M, Kayser M, Palstra RJ. HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res. 2012;22:446–55.

    Article  CAS  Google Scholar 

  16. Ferguson R, Vogelsang M, Ucisik-Akkaya E, et al. Genetic markers of pigmentation are novel risk loci for uveal melanoma. Sci Rep. 2016;6:31191.

    Article  CAS  Google Scholar 

  17. Simpson ER, Gallie BL, Saakyan S, et al. International validation of the American Joint Committee on Cancer’s 7th edition classification of uveal melanoma. JAMA Ophthalmol. 2015;133:376–83.

    Article  Google Scholar 

  18. Whelchel JC, Farah SE, McLean IW, Burnier M. Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Investig Ophthalmol Vis Sci. 1993;34:2603–6.

    CAS  Google Scholar 

  19. Thomas NE, Kricker A, Waxweiler WT, et al. Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas. JAMA Dermatol. 2014;150:1306–14.

    Article  Google Scholar 

  20. Singh L, Singh MK, Rizvi MA, et al. Prognostic significance of immune checkpoints in the tumour-stromal microenvironment of sebaceous gland carcinoma. Br J Ophthalmol. 2020. https://doi.org/10.1136/bjophthalmol-2019-315490.

    Article  PubMed  Google Scholar 

  21. Janjetovic Z, Brozyna AA, Tuckey RC, et al. High basal NF-kappaB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives. Br J Cancer. 2010;105:1874–84.

    Article  Google Scholar 

  22. Slominski A, Kim TK, Brozyna AA, et al. The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1alpha expression and HIF-dependent attendant pathways. Arch Biochem Biophys. 2014;563:79–93.

    Article  CAS  Google Scholar 

  23. Shields CL, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields JA. American joint committee on cancer classification of uveal melanoma (anatomic stage) predicts prognosis in 7731 patients. Ophthalmology. 2015;122:1180–6.

    Article  Google Scholar 

  24. Rothermel LD, Sabesan AC, Stephens DJ, Chandran SS, Paria BC, Srivastava AK, Somerville R, Wunderlich JR, Lee CC, Xi L, Pham TH. Identification of an immunogenic subset of metastatic uveal melanoma. Clin Cancer Res. 2016;22(9):2237–49.

    Article  CAS  Google Scholar 

  25. Coupland SE, Campbell I, Damato B. Routes of extraocular extension of uveal melanoma risk factors and influence on survival probability. Ophthalmology. 2008;115:1778–855.

    Article  Google Scholar 

  26. Lee DS, Anderson SF, Perez EM, Townsend JC. Amelanotic choroidal nevus and melanoma: cytology, tumor size, and pigmentation as prognostic indicators. Optom Vis Sci. 2001;78:7.

    Article  Google Scholar 

  27. Seddon JM, Albert DM, Lavin PT, Robinson N. A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol. 1983;101:1894–9.

    Article  CAS  Google Scholar 

  28. Ibarrola-Villava M, Fernandez LP, Pita G, et al. Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2. Exp Dermatol. 2010;19:836–44.

    Article  CAS  Google Scholar 

  29. Kaliki S, Shields CL, Shields JA. Uveal melanoma: estimating prognosis. Indian J Ophthalmol. 2015;63:93–102.

    Article  Google Scholar 

  30. Brozyna AA, Jozwicki W, Carlson JA, Slominski AT. Melanogenesis affects overall and disease-free survival in patients with stage III and IV melanoma. Hum Pathol. 2013;44:2071–4.

    Article  Google Scholar 

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Funding

This research was funded by Intramural Research Grant (IRG), All India Institute of Medical Sciences, New Delhi (F.8-636/A-636/2018/RS).

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Authors and Affiliations

  1. Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, New Delhi, India

    Seema Kashyap, Mithalesh Kumar Singh, Jayanti Jha, Lata Singh & Seema Sen

  2. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi, India

    Neelam Pushker, Pradeep Venkatesh, Rachna Meel & Neiwete Lomi

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  1. Seema Kashyap
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  2. Mithalesh Kumar Singh
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  3. Jayanti Jha
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  4. Lata Singh
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  6. Seema Sen
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  9. Neiwete Lomi
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Correspondence to Neiwete Lomi.

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The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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This research involved the human participants. All procedures were approved by the institutional ethics committee, All India Institute of Medical Sciences (AIIMS), New Delhi, India (IEC-472/07.09.2018).

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Written informed consent was obtained from all patients before participation in this study.

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Kashyap, S., Singh, M.K., Jha, J. et al. Prognostic impact of HERC2 protein and pink-eyed dilution protein in uveal melanoma. Human Cell 33, 1264–1272 (2020). https://doi.org/10.1007/s13577-020-00397-9

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  • DOI: https://doi.org/10.1007/s13577-020-00397-9

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