Skip to main content
Log in

Immunohistochemical expression of PRAME in 485 cases of epithelial tubo-ovarian tumors

  • ORIGINAL ARTICLE
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Preferentially expressed antigen of melanoma (PRAME) is a cancer/testis antigen selectively expressed in somatic tissues and various solid malignant tumors and is associated with poor prognostic outcome. Our research aimed to comprehensively compare its expression in a large cohort of tubo-ovarian epithelial tumors and examine its correlation with our clinico-pathologic data, as well as to assess its potential use in diagnostics and therapy.

We examined 485 cases of epithelial tubo-ovarian tumors including 107 clear cell carcinomas (CCC), 52 endometroid carcinomas (EC), 103 high grade serous carcinomas (HGSC), 119 low grade serous carcinomas (LGSC)/micropapillary variant of serous borderline tumors (mSBT), and 104 cases of mucinous carcinomas (MC)/mucinous borderline tumors (MBT). The immunohistochemical analysis was performed using TMAs.

The highest levels of expression were seen in EC (60%), HGSC (62%), and CCC (56%), while expression in LGSC/mSBT (4%) and MC/MBT (2%) was rare. The clinico-pathologic correlations and survival analysis showed no prognostic significance.

The results of our study showed that PRAME is neither prognostic nor a suitable ancillary marker in the differential diagnosis of tubo-ovarian epithelial tumors. Nevertheless, knowledge about the PRAME expression may be important concerning its potential predictive significance, because targeting PRAME as a potential therapeutic option is currently under investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

All data generated or analyzed during this study is included in this published article (and its Supplementary information files).

References

  1. Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188:22–32. https://doi.org/10.1034/j.1600-065x.2002.18803.x

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Caballero OL, Chen Y-T (2009) Cancer/testis (CT) antigens: Potential targets for immunotherapy. Cancer Sci 100:2014–2021. https://doi.org/10.1111/j.1349-7006.2009.01303.x

    Article  CAS  PubMed  Google Scholar 

  4. Yao J, Caballero OL, Yung WK, Weinstein JN, Riggins GJ, Strausberg RL, Zhao Q (2014) Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers. Cancer Immunol Res 2(4):371–379. https://doi.org/10.1158/2326-6066.CIR-13-0088

    Article  CAS  PubMed  Google Scholar 

  5. Li J, Yin J, Zhong J, Yang Z, Tang A, Li S (2020) Clinicopathological and Prognostic Significance of PRAME Overexpression in Human Cancer: A Meta-Analysis. Biomed Res Int 2020:8828579. https://doi.org/10.1155/2020/8828579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, Allen RE, Singer MI, Leong SP, Ljung BM, Sagebiel RW, Kashani-Sabet M (2005) The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A 102(17):6092–6097. https://doi.org/10.1073/pnas.0501564102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mirjam T (2006) Epping, René Bernards; A Causal Role for the Human Tumor Antigen Preferentially Expressed Antigen of Melanoma in Cancer. Cancer Res 66(22):10639–10642. https://doi.org/10.1158/0008-5472.CAN-06-2522

    Article  CAS  Google Scholar 

  8. Neumann E, Engelsberg A, Decker J, Störkel S, Jaeger E, Huber C, Seliger B (1998) Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: candidates for T-cell-based immunotherapies? Cancer Res 58(18):4090–4095

    CAS  PubMed  Google Scholar 

  9. Bankovic J, Stojsic J, Jovanovic D, Andjelkovic T, Milinkovic V, Ruzdijic S, Tanic N (2010) Identification of genes associated with non-small-cell lung cancer promotion and progression. Lung Cancer 67(2):151–159. https://doi.org/10.1016/j.lungcan.2009.04.010

    Article  PubMed  Google Scholar 

  10. Oberthuer A, Hero B, Spitz R, Berthold F, Fischer M (2004) The tumor-associated antigen PRAME is universally expressed in high-stage neuroblastoma and associated with poor outcome. Clin Cancer Res 10(13):4307–4313. https://doi.org/10.1158/1078-0432.CCR-03-0813

    Article  CAS  PubMed  Google Scholar 

  11. Doolan P, Clynes M, Kennedy S, Mehta JP, Crown J, O’Driscoll L (2008) Prevalence and prognostic and predictive relevance of PRAME in breast cancer. Breast Cancer Res Treat 109(2):359–365. https://doi.org/10.1007/s10549-007-9643-3

    Article  CAS  PubMed  Google Scholar 

  12. Roszik J, Wang WL, Livingston JA, Roland CL, Ravi V, Yee C, Hwu P, Futreal A, Lazar AJ, Patel SR, Conley AP (2017) Overexpressed PRAME is a potential immunotherapy target in sarcoma subtypes. Clin Sarcoma Res 7:11. https://doi.org/10.1186/s13569-017-0077-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gezgin G, Luk SJ, Cao J, Dogrusöz M, van der Steen DM, Hagedoorn RS, Krijgsman D, van der Velden PA, Field MG, Luyten GPM, Szuhai K, Harbour JW, Jordanova ES, Heemskerk MHM, Jager MJ (2017) PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma. JAMA Ophthalmol 135(6):541–549. https://doi.org/10.1001/jamaophthalmol.2017.0729

    Article  PubMed  PubMed Central  Google Scholar 

  14. Santamaría C, Chillón MC, García-Sanz R, Balanzategui A, Sarasquete ME, Alcoceba M, Ramos F, Bernal T, Queizán JA, Peñarrubia MJ, Giraldo P, San Miguel JF, Gonzalez M (2008) The relevance of preferentially expressed antigen of melanoma (PRAME) as a marker of disease activity and prognosis in acute promyelocytic leukemia. Haematologica 93(12):1797–1805. https://doi.org/10.3324/haematol.13214

    Article  PubMed  Google Scholar 

  15. Steinbach D, Hermann J, Viehmann S, Zintl F, Gruhn B (2002) Clinical implications of PRAME gene expression in childhood acute myeloid leukemia. Cancer Genet Cytogenet 133(2):118–123. https://doi.org/10.1016/s0165-4608(01)00570-2

    Article  CAS  PubMed  Google Scholar 

  16. Abdelmalak CA, Yahya RS, Elghannam DM, El-Khadragy AE, Abd-El-Messih HM (2014) PRAME gene expression in childhood acute lymphoblastic leukemia: impact on prognosis. Clin Lab 60(1):55–61. https://doi.org/10.7754/clin.lab.2013.121137

    Article  CAS  PubMed  Google Scholar 

  17. Schenk T, Stengel S, Goellner S, Steinbach D, Saluz HP (2007) Hypomethylation of PRAME is responsible for its aberrant overexpression in human malignancies. Genes Chromosomes Cancer 46(9):796–804. https://doi.org/10.1002/gcc.20465

    Article  CAS  PubMed  Google Scholar 

  18. Lee YK, Park UH, Kim EJ, Hwang JT, Jeong JC, Um SJ (2017) Tumor antigen PRAME is up-regulated by MZF1 in cooperation with DNA hypomethylation in melanoma cells. Cancer Lett 403:144–151. https://doi.org/10.1016/j.canlet.2017.06.015

    Article  CAS  PubMed  Google Scholar 

  19. Sakurai E, Maesawa C, Shibazaki M, Yasuhira S, Oikawa H, Sato M, Tsunoda K, Ishikawa Y, Watanabe A, Takahashi K, Akasaka T, Masuda T (2011) Downregulation of microRNA-211 is involved in expression of preferentially expressed antigen of melanoma in melanoma cells. Int J Oncol 39(3):665–672. https://doi.org/10.3892/ijo.2011.1084

    Article  CAS  PubMed  Google Scholar 

  20. Lezcano C, Jungbluth AA, Nehal KS, Hollmann TJ, Busam KJ (2018) PRAME Expression in Melanocytic Tumors. Am J Surg Pathol 42(11):1456–1465. https://doi.org/10.1097/PAS.0000000000001134

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lezcano C, Müller AM, Frosina D, Hernandez E, Geronimo JA, Busam KJ, Jungbluth AA (2021) Immunohistochemical Detection of Cancer-Testis Antigen PRAME. Int J Surg Pathol 29(8):826–835. https://doi.org/10.1177/10668969211012085

    Article  CAS  PubMed  Google Scholar 

  22. Kaczorowski M, Chłopek M, Kruczak A, Ryś J, Lasota J, Miettinen M (2022) PRAME Expression in Cancer. A Systematic Immunohistochemical Study of >5800 Epithelial and Nonepithelial Tumors. Am J Surg Pathol. 46(11):1467–1476. https://doi.org/10.1097/PAS.0000000000001944

    Article  PubMed  Google Scholar 

  23. Dundr P, Bazalová B, Bártů M, Bosse T, Drozenová J, Fabian P, Fadare O, Hausnerová J, Jakša R, Laco J, Lax SF, Matěj R, McCluggage WG, Méhes G, Michálková R, Němejcová K, Singh N, Stolnicu S, Škapa P, Švajdler M, Stružinská I (2022) The cytokeratin 17 expression in primary ovarian tumors has diagnostic but not prognostic significance. Virchows Arch 481(2):201–212. https://doi.org/10.1007/s00428-022-03338-z

    Article  CAS  PubMed  Google Scholar 

  24. Kunc M, Żemierowska N, Skowronek F, Biernat W (2023) Diagnostic test accuracy meta-analysis of PRAME in distinguishing primary cutaneous melanomas from benign melanocytic lesions. Histopathology 83(1):3–14. https://doi.org/10.1111/his.14904

    Article  PubMed  Google Scholar 

  25. Weber JS, Vogelzang NJ, Ernstoff MS, Goodman OB, Cranmer LD, Marshall JL, Miles S, Rosario D, Diamond DC, Qiu Z, Obrocea M, Bot A (2011) A phase 1 study of a vaccine targeting preferentially expressed antigen in melanoma and prostate-specific membrane antigen in patients with advanced solid tumors. J Immunother 34(7):556–567. https://doi.org/10.1097/CJI.0b013e3182280db1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gutzmer R, Rivoltini L, Levchenko E, Testori A, Utikal J, Ascierto PA, Demidov L, Grob JJ, Ridolfi R, Schadendorf D, Queirolo P, Santoro A, Loquai C, Dreno B, Hauschild A, Schultz E, Lesimple TP, Vanhoutte N, Salaun B, Gillet M, Jarnjak S, De Sousa Alves PM, Louahed J, Brichard VG, Lehmann FF (2016) Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study. ESMO Open 1(4):e000068. https://doi.org/10.1136/esmoopen-2016-000068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Al-Khadairi G, Decock J (2019) Cancer Testis Antigens and Immunotherapy: Where Do We Stand in the Targeting of PRAME? Cancers (Basel) 11(7):984. https://doi.org/10.3390/cancers11070984

    Article  CAS  PubMed  Google Scholar 

  28. Naik A, Thomas R, Al-Khadairi G, Bacha R, Hendrickx W, Decock J (2021) Cancer testis antigen PRAME: An anti-cancer target with immunomodulatory potential. J Cell Mol Med 25(22):10376–10388. https://doi.org/10.1111/jcmm.16967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang W, Barger CJ, Eng KH, Klinkebiel D, Link PA, Omilian A, Bshara W, Odunsi K, Karpf AR (2016) PRAME expression and promoter hypomethylation in epithelial ovarian cancer. Oncotarget 7(29):45352–45369. https://doi.org/10.18632/oncotarget.9977

    Article  PubMed  PubMed Central  Google Scholar 

  30. Brenne K, Nymoen DA, Reich R, Davidson B (2012) PRAME (preferentially expressed antigen of melanoma) is a novel marker for differentiating serous carcinoma from malignant mesothelioma. Am J Clin Pathol 137(2):240–247. https://doi.org/10.1309/AJCPGA95KVSAUDMF

    Article  CAS  PubMed  Google Scholar 

  31. Partheen K, Levan K, Osterberg L, Claesson I, Fallenius G, Sundfeldt K, Horvath G (2008) Four potential biomarkers as prognostic factors in stage III serous ovarian adenocarcinomas. Int J Cancer 123(9):2130–2137. https://doi.org/10.1002/ijc.23758

    Article  CAS  PubMed  Google Scholar 

  32. Coppock JD, Gradecki SE, Mills AM (2023) PRAME Expression in Endometrioid and Serous Endometrial Carcinoma: A Potential Immunotherapeutic Target and Possible Diagnostic Pitfall. Int J Gynecol Pathol 42(1):35–42. https://doi.org/10.1097/PGP.0000000000000864

    Article  CAS  PubMed  Google Scholar 

  33. Němejcová K, Šafanda A, Bártů MK, Michálková R, Drozenová J, Fabian P, Hausnerová J, Laco J, Matěj R, Méhes G, Škapa P, Stružinská I, Dundr P (2023) A comprehensive immunohistochemical analysis of 26 markers in 250 cases of serous ovarian tumors. Diagn Pathol 18(1):32. https://doi.org/10.1186/s13000-023-01317-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dundr P, Bártů M, Bosse T, Bui QH, Cibula D, Drozenová J, Fabian P, Fadare O, Hausnerová J, Hojný J, Hájková N, Jakša R, Laco J, Lax SF, Matěj R, Méhes G, Michálková R, Šafanda A, Němejcová K, Singh N, Stolnicu S, Švajdler M, Zima T, Stružinská I, McCluggage WG (2023) Primary Mucinous Tumors of the Ovary: An Interobserver Reproducibility and Detailed Molecular Study Reveals Significant Overlap Between Diagnostic Categories. Mod Pathol 36(1):100040. https://doi.org/10.1016/j.modpat.2022.100040

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Ministry of Health, Czech Republic (RVO VFN 64165 and AZV NV19-03–00007), by Charles University (Project UNCE204065, SVV260631), and by the European Regional Development Fund (EF16_013/0001674 and BBMRI_CZ LM2023033).

Author information

Authors and Affiliations

Authors

Contributions

Pavel Dundr and Kristýna Němejcová performed the study concept and design. All authors participated on material preparation, data collection, and / or analyses. Romana Michálková provided statistical analysis. The first draft of the manuscript was written by Adam Šafanda. All authors commented on previous versions of the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Kristýna Němejcová.

Ethics declarations

Ethics approval

The study was approved by the Ethics Committee of the General University Hospital in Prague in compliance with the Helsinki Declaration (No. 2140/19 S-IV). The Ethics Committee waived the requirement for informed consent as according to the Czech Law (Act. no. 373/11, and its amendment Act no. 202/17), it is not necessary to obtain informed consent in fully anonymized studies.

Consent to participate

Not applicable.

Competing interests

The authors declare no competing financial and/or non-financial interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 22 KB)

Supplementary file2 (DOCX 16 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Šafanda, A., Kendall Bártů, M., Michálková, R. et al. Immunohistochemical expression of PRAME in 485 cases of epithelial tubo-ovarian tumors. Virchows Arch 483, 509–516 (2023). https://doi.org/10.1007/s00428-023-03629-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-023-03629-z

Keywords

Navigation