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Diagnostic utility of immunohistochemistry in concordance with mRNA analysis of PRAME in the stratification of high-risk uveal melanoma patients

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Abstract

Existing clinical indicators for metastatic risk classification and patient treatment of uveal melanoma (UM) in the Asian population are limited. Preferentially expressed antigen in melanoma (PRAME) has gained attention in the prognosis of cancers and considered as a potential biomarker in many tumors including UM. Therefore, this study investigated the expression of PRAME and its association with loss of nuclear BAP1 (nBAP1) as well as its correlation with clinicopathological parameters and patient outcome. Immunohistochemical expression of PRAME and BAP1 proteins were assessed in 66 prospective cases of UM. mRNA expression level was measured by quantitative real-time PCR. Kaplan–Meier curves and Cox proportional hazard models were used to analyze the correlation of protein expression with clinicopathological parameters, metastasis-free survival and overall survival. Nuclear PRAME (nPRAME) expression and loss of nBAP1 were observed in 24 and 62% cases, respectively. PRAME mRNA expression level was found to be upregulated in 64% (7/11) of metastatic patients. mRNA and immunoexpression of nPRAME were statistically significant with many clinicopathological high-risk factors. On univariate and multivariate analyses, high mitotic activity, extraocular invasion and presence of nPRAME expression were statistically significant (p < 0.05). On Kaplan–Meier survival analysis, patients expressing PRAME had significantly reduced metastasis-free survival (MFS) and overall survival (OS). MFS and OS were also reduced in patients expressing PRAME along with loss of nBAP1. Our data show that nPRAME expression, in combination with loss of nBAP1, could be a useful predictive biomarker in the therapeutic management of UM patients at high risk.

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References

  1. Lee WS, Lee J, Choi JJ, Kang HG, Lee SC, Kim JH. Paired comparisons of mutational profiles before and after brachytherapy in asian uveal melanoma patients. Sci Rep. 2021;11(1):18594. https://doi.org/10.1038/s41598-021-98084-8.

    Article  CAS  Google Scholar 

  2. Branisteanu DC, Bogdanici CM, Branisteanu DE, Maranduca MA, Zemba M, Balta F, et al. Uveal melanoma diagnosis and current treatment options (Review). Exp Ther Med. 2021;22(6):1428. https://doi.org/10.3892/etm.2021.10863.

    Article  CAS  Google Scholar 

  3. Jager MJ, Shields CL, Cebulla CM, Abdel-Rahman MH, Grossniklaus HE, Stern MH, et al. Uveal melanoma. Nat Rev Dis Primers. 2020;6(1):24. https://doi.org/10.1038/s41572-020-0158-0.

    Article  Google Scholar 

  4. Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64(20):7205–9. https://doi.org/10.1158/0008-5472.Can-04-1750.

    Article  CAS  Google Scholar 

  5. Harbour JW. A prognostic test to predict the risk of metastasis in uveal melanoma based on a 15-gene expression profile. Methods Mol Biol. 2014;1102:427–40. https://doi.org/10.1007/978-1-62703-727-3_22.

    Article  CAS  Google Scholar 

  6. van Essen TH, van Pelt SI, Versluis M, Bronkhorst IH, van Duinen SG, Marinkovic M, et al. Prognostic parameters in uveal melanoma and their association with BAP1 expression. Br J Ophthalmol. 2014;98(12):1738–43. https://doi.org/10.1136/bjophthalmol-2014-305047.

    Article  Google Scholar 

  7. Aaberg TM, Covington KR, Tsai T, Shildkrot Y, Plasseraud KM, Alsina KM, et al. Gene expression profiling in uveal melanoma: five-year prospective outcomes and meta-analysis. Ocul Oncol Pathol. 2020;6(5):360–7. https://doi.org/10.1159/000508382.

    Article  Google Scholar 

  8. Field MG, Decatur CL, Kurtenbach S, Gezgin G, van der Velden PA, Jager MJ, et al. PRAME as an independent biomarker for metastasis in uveal melanoma. Clin Cancer Res. 2016;22(5):1234–42. https://doi.org/10.1158/1078-0432.Ccr-15-2071.

    Article  CAS  Google Scholar 

  9. Lezcano C, Jungbluth AA, Nehal KS, Hollmann TJ, Busam KJ. PRAME expression in melanocytic tumors. Am J Surg Pathol. 2018;42(11):1456–65. https://doi.org/10.1097/pas.0000000000001134.

    Article  Google Scholar 

  10. Szczepanski MJ, DeLeo AB, Łuczak M, Molinska-Glura M, Misiak J, Szarzynska B, et al. PRAME expression in head and neck cancer correlates with markers of poor prognosis and might help in selecting candidates for retinoid chemoprevention in pre-malignant lesions. Oral Oncol. 2013;49(2):144–51. https://doi.org/10.1016/j.oraloncology.2012.08.005.

    Article  CAS  Google Scholar 

  11. Thongprasert S, Yang PC, Lee JS, Soo R, Gruselle O, Myo A, et al. The prevalence of expression of MAGE-A3 and PRAME tumor antigens in East and South East Asian non-small cell lung cancer patients. Lung Cancer. 2016;101:137–44. https://doi.org/10.1016/j.lungcan.2016.09.006.

    Article  Google Scholar 

  12. Epping MT, Hart AA, Glas AM, Krijgsman O, Bernards R. PRAME expression and clinical outcome of breast cancer. Br J Cancer. 2008;99(3):398–403. https://doi.org/10.1038/sj.bjc.6604494.

    Article  CAS  Google Scholar 

  13. Lezcano C, Pulitzer M, Moy AP, Hollmann TJ, Jungbluth AA, Busam KJ. Immunohistochemistry for PRAME in the distinction of nodal nevi from metastatic melanoma. Am J Surg Pathol. 2020;44(4):503–8. https://doi.org/10.1097/pas.0000000000001393.

    Article  Google Scholar 

  14. Toyama A, Siegel L, Nelson AC, Najmuddin M, Bu L, LaRue R, et al. Analyses of molecular and histopathologic features and expression of PRAME by immunohistochemistry in mucosal melanomas. Mod Pathol. 2019;32(12):1727–33. https://doi.org/10.1038/s41379-019-0335-4.

    Article  CAS  Google Scholar 

  15. Lohman ME, Steen AJ, Grekin RC, North JP. The utility of PRAME staining in identifying malignant transformation of melanocytic nevi. J Cutan Pathol. 2021;48(7):856–62. https://doi.org/10.1111/cup.13958.

    Article  Google Scholar 

  16. Coupland S, Kalirai H, Taktak A, Eleuteri A, Damato B. Re: Gelmi et al adding the cancer genome atlas chromosome classes to American Joint Committee on Cancer System offers more precise prognostication in uveal melanoma. Ophthalmology. 2022. https://doi.org/10.1016/j.ophtha.2022.02.031.

    Article  Google Scholar 

  17. Kapoor AG, Kaliki S, Vempuluru VS, Jajapuram SD, Ali MH, Mohamed A. (2020) Posterior uveal melanoma in 321 Asian Indian patients: analysis based on the 8th edition of American Joint Committee Cancer classification. Int Ophthalmol. 40(11): 3087-3096 https://doi.org/10.1007/s10792-020-01494-2

  18. Jha J, Singh MK, Singh L, Pushker N, Bajaj MS, Sen S, et al. Expression of BAP1 and ATM proteins: association with AJCC tumor category in uveal melanoma. Ann Diagn Pathol. 2020;44: 151432. https://doi.org/10.1016/j.anndiagpath.2019.151432.

    Article  Google Scholar 

  19. Ahmadian SS, Dryden IJ, Naranjo A, Toland A, Cayrol RA, Born DE, et al. Preferentially expressed antigen in melanoma immunohistochemistry labeling in uveal melanomas. Ocul Oncol Pathol. 2022;8(2):133–40. https://doi.org/10.1159/000524051.

    Article  Google Scholar 

  20. See TR, Stålhammar G, Phillips S, Grossniklaus HE. BAP1 immunoreactivity correlates with gene expression class in uveal melanoma. Ocul Oncol Pathol. 2020;6(2):129–37. https://doi.org/10.1159/000502550.

    Article  Google Scholar 

  21. Kaštelan S, Antunica AG, Oresković LB, Pelčić G, Kasun E, Hat K. Immunotherapy for uveal melanoma - current knowledge and perspectives. Curr Med Chem. 2020;27(8):1350–66. https://doi.org/10.2174/0929867326666190704141444.

    Article  CAS  Google Scholar 

  22. Schefler AC, Koca E, Bernicker EH, Correa ZM. Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma. Graefes Arch Clin Exp Ophthalmol. 2019;257(7):1541–5. https://doi.org/10.1007/s00417-019-04335-w.

    Article  CAS  Google Scholar 

  23. Cai L, Paez-Escamilla M, Walter SD, Tarlan B, Decatur CL, Perez BM, et al. Gene expression profiling and PRAME status versus tumor-node-metastasis staging for prognostication in uveal melanoma. Am J Ophthalmol. 2018;195:154–60. https://doi.org/10.1016/j.ajo.2018.07.045.

    Article  CAS  Google Scholar 

  24. Ikeda H, Lethé B, Lehmann F, van Baren N, Baurain JF, de Smet C, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6(2):199–208. https://doi.org/10.1016/s1074-7613(00)80426-4.

    Article  CAS  Google Scholar 

  25. Chang AY, Dao T, Gejman RS, Jarvis CA, Scott A, Dubrovsky L, et al. A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. J Clin Invest. 2017;127(7):2705–18. https://doi.org/10.1172/jci92335.

    Article  Google Scholar 

  26. Wadelin F, Fulton J, McEwan PA, Spriggs KA, Emsley J, Heery DM. Leucine-rich repeat protein PRAME: expression, potential functions and clinical implications for leukaemia. Mol Cancer. 2010;9:226. https://doi.org/10.1186/1476-4598-9-226.

    Article  CAS  Google Scholar 

  27. Baba H, Kanda M, Sawaki K, Umeda S, Miwa T, Shimizu D, et al. PRAME as a potential biomarker for liver metastasis of gastric cancer. Ann Surg Oncol. 2020;27(6):2071–80. https://doi.org/10.1245/s10434-019-07985-6.

    Article  Google Scholar 

  28. Ding K, Wang XM, Fu R, Ruan EB, Liu H, Shao ZH. PRAME gene expression in acute leukemia and its clinical significance. Cancer Biol Med. 2012;9(1):73–6. https://doi.org/10.3969/j.issn.2095-3941.2012.01.013.

    Article  CAS  Google Scholar 

  29. Cazzato G, Mangialardi K, Falcicchio G, Colagrande A, Ingravallo G, Arezzo F, et al. Preferentially expressed antigen in melanoma (PRAME) and human malignant melanoma: a retrospective study. Genes. 2022;13(3):545. https://doi.org/10.3390/genes13030545.

    Article  CAS  Google Scholar 

  30. Zhang YH, Lu AD, Yang L, Li LD, Chen WM, Long LY, et al. PRAME overexpression predicted good outcome in pediatric B-cell acute lymphoblastic leukemia patients receiving chemotherapy. Leuk Res. 2017;52:43–9. https://doi.org/10.1016/j.leukres.2016.11.005.

    Article  CAS  Google Scholar 

  31. Al-Khadairi G, Naik A, Thomas R, Al-Sulaiti B, Rizly S, Decock J. PRAME promotes epithelial-to-mesenchymal transition in triple negative breast cancer. J Transl Med. 2019;17(1):9. https://doi.org/10.1186/s12967-018-1757-3.

    Article  Google Scholar 

  32. Field MG, Durante MA, Decatur CL, Tarlan B, Oelschlager KM, Stone JF, et al. Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas. Oncotarget. 2016;7(37):59209–19. https://doi.org/10.18632/oncotarget.10962.

    Article  Google Scholar 

  33. Bronkhorst IH, Jager MJ. Uveal melanoma: the inflammatory microenvironment. J Innate Immun. 2012;4(5–6):454–62. https://doi.org/10.1159/000334576.

    Article  CAS  Google Scholar 

  34. Mlecnik B, Bindea G, Pagès F, Galon J. Tumor immunosurveillance in human cancers. Cancer Metastasis Rev. 2011;30(1):5–12. https://doi.org/10.1007/s10555-011-9270-7.

    Article  CAS  Google Scholar 

  35. Xu Q, Wang C, Yuan X, Feng Z, Han Z. Prognostic value of tumor-infiltrating lymphocytes for patients with head and neck squamous cell carcinoma. Transl Oncol. 2017;10(1):10–6. https://doi.org/10.1016/j.tranon.2016.10.005.

    Article  Google Scholar 

  36. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, et al. The prognostic value of peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Int. 2009;103(3):399–405. https://doi.org/10.1111/j.1464-410X.2008.08151.x.

    Article  Google Scholar 

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Acknowledgements

Nikhil Kumar is thankful to the Indian Council of Medical Research for providing Junior Research Fellowship.

Funding

This research was funded by Indian Council of Medical Research (F. No. 5/4/6/3/OPH/2019-NCD-II).

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Author notes

  1. Nikhil Kumar and Mithalesh Kumar Singh have contributed equally to this work.

Authors and Affiliations

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

    Nikhil Kumar, Seema Sen & Seema Kashyap

  2. Department of Ophthalmology, University of California, Irvine, CA, USA

    Mithalesh Kumar Singh

  3. Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

    Lata Singh

  4. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    Neiwete Lomi, Rachna Meel & Neelam Pushker

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Contributions

MKS and SK were responsible for the conception and design of the work. NK, LS and MKS contributed to the acquisition, analysis, and interpretation of data for the work. NL and RM provided the enucleated specimens. SS and SK helped in reviewing the histopathology slides. All the authors reviewed and approved the final version of the manuscript.

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Correspondence to Lata Singh or Seema Kashyap.

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Ethical approval was obtained from the Institute’s Ethical Committee, All India Institute of Medical Sciences (Ref. No. IEC-189/05–04-2019).

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

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Kumar, N., Singh, M.K., Singh, L. et al. Diagnostic utility of immunohistochemistry in concordance with mRNA analysis of PRAME in the stratification of high-risk uveal melanoma patients. Human Cell 36, 342–352 (2023). https://doi.org/10.1007/s13577-022-00808-z

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