Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma

  • Amy C. ScheflerEmail author
  • Emre Koca
  • Eric H. Bernicker
  • Zelia M. Correa



Metastatic risk for uveal melanoma (UM) patients can be characterized by gene expression profiling (GEP) (Castle Biosciences, Friendswood, TX). Class 1A tumors carry low metastatic risk; class 1B tumors have intermediate risk; and class 2 tumors have high risk. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen which is expressed in various neoplasms including UM. Recently, PRAME expression in uveal melanoma was first recognized to confer an additional metastatic risk beyond GEP status.


This was a retrospective, consecutive, multicenter chart review study. All patients diagnosed with UM at two major ocular oncology centers from August 2016 to February 2018 who underwent both GEP and PRAME mRNA expression testing were included. Patient age at diagnosis, gender, and tumor variables such as thickness, largest basal diameter (LBD), tumor volume, TNM stage, and GEP class and PRAME status were extracted from the medical records. Statistical analysis was performed to analyze the association of PRAME +/− status with all clinical and molecular variables.


One hundred forty-eight UM patients were identified. TNM was stage I in 51 (34.5%), stage IIA in 33 (22.3%), stage IIB in 34 (23%), stage IIIA in 20 (13.5%), and stage IIIB in 10 (6.8%) patients. Fifty-five patients (37%) were PRAME-positive, a significant fraction. There was no association between higher TNM stage and positive PRAME status (p = 0.129). PRAME expression was found to be independent of gender, patient age, and tumor thickness. PRAME expression was statistically associated with LBD and tumor volume. Higher GEP class was associated with higher TNM staging (p < 0.001). Worsening GEP class was associated with PRAME+ status with 28% of GEP class 1A tumors having PRAME+ status, 29% of GEP class 1B tumors having PRAME+ status, and 56% of GEP class 2 tumors having PRAME+ status.


In this study cohort, PRAME+ status was significantly associated with LBD and tumor volume as well as worsening GEP class. Nearly a third of GEP class 1A tumors expressed PRAME. Given the recent published data on increased metastatic risk among patients with tumors expressing PRAME, this study suggests that a significant fraction of 1A patients may harbor an increased metastatic risk. Future large, multicenter studies with long-term follow-up will clarify this finding.


Uveal melanoma PRAME Tumor genetics Cancer genetics Mortality 



The authors wish to thank Richard Vestewig, Ph.D., of GSRV Associates, LLC, who contributed to the statistical analysis. He was compensated for his contributions.

Compliance with ethical standards

Conflict of interest

ACS—Genentech (Consultant, Grant Funding), Regeneron (Grant Funding), Aura Biosciences (Consultant, Grant Funding), Castle Biosciences (Grant Funding—not for this study); EK—none; EHB—Guardant Health (Advisory Board), Abbvie (Advisory Board), Astra Zeneca (Advisory Board); ZMC—Castle Biosciences (Consultant).

Ethical approval

All procedures in this study was in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Collaborative Ocular Melanoma Study G (2001) Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch Ophthalmol 119:670–676CrossRefGoogle Scholar
  2. 2.
    Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM et al (2012) Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 119:1596–1603CrossRefGoogle Scholar
  3. 3.
    Onken MD, Worley LA, Tuscan MD, Harbour JW (2010) An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 12:461–468CrossRefGoogle Scholar
  4. 4.
    Field MG, Decatur CL, Kurtenbach S, Gezgin G, van der Velden PA et al (2016) PRAME as an independent biomarker for metastasis in uveal melanoma. Clin Cancer Res 22:1234–1242CrossRefGoogle Scholar
  5. 5.
    Field MG, Durante MA, Decatur CL, Tarlan B, Oelschlager KM et al (2016) Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in class 1 and class 2 uveal melanomas. Oncotarget 7:59209–59219CrossRefGoogle Scholar
  6. 6.
    Faustino-Rocha A, Oliveira PA, Pinho-Oliveira J, Teixeira-Guedes C, Soares-Maia R et al (2013) Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. Lab Anim (NY) 42:217–224CrossRefGoogle Scholar
  7. 7.
    American Joint Committee on Cancer. references-tools/deskreferences/Pages/Supplementary-Material.aspx Accessed 5 Feb 2019
  8. 8.
    Cuzick J (1985) A Wilcoxon-type test for trendGoogle Scholar
  9. 9.
    Correa ZM, Augsburger JJ (2016) Independent prognostic significance of gene expression profile class and largest basal diameter of posterior uveal melanomas. Am J Ophthalmol 162:20–7 e1CrossRefGoogle Scholar
  10. 10.
    Ikeda H, Lethe B, Lehmann F, van Baren N, Baurain JF et al (1997) Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 6:199–208CrossRefGoogle Scholar
  11. 11.
    Epping MT, Hart AA, Glas AM, Krijgsman O, Bernards R (2008) PRAME expression and clinical outcome of breast cancer. Br J Cancer 99:398–403CrossRefGoogle Scholar
  12. 12.
    Cai L, Paez-Escamilla M, Walter SD, Tarlan B, Decatur CL et al (2018) Gene expression profiling and PRAME status versus tumor-node-metastasis staging for prognostication in uveal melanoma. Am J Ophthalmol 195:154–160CrossRefGoogle Scholar
  13. 13.
    McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW (2005) Incidence of noncutaneous melanomas in the U.S. Cancer 103:1000–1007CrossRefGoogle Scholar
  14. 14.
    Nguyen BT, Kim RS, Bretana ME, Kegley E, Schefler AC (2018) Association between traditional clinical high-risk features and gene expression profile classification in uveal melanoma. Graefes Arch Clin Exp Ophthalmol 256:421–427CrossRefGoogle Scholar
  15. 15.
    Berry D, Seider M, Stinnett S, Mruthyunjaya P, Schefler AC, Ocular Oncology Study C. (2018. Relationship of clinical features and baseline tumor size with gene expression profile status in uveal melanoma: a multi-institutional Study. RetinaGoogle Scholar
  16. 16.
    Harbour JW (2017) Incorporating clinical, histological, and genetic parameters for choroidal melanoma prognostication-reply. JAMA ophthalmol 135:819–820CrossRefGoogle Scholar
  17. 17.
    Correa ZM, Augsburger JJ (2014) Sufficiency of FNAB aspirates of posterior uveal melanoma for cytologic versus GEP classification in 159 patients, and relative prognostic significance of these classifications. Graefes Arch Clin Exp Ophthalmol 252:131–135CrossRefGoogle Scholar
  18. 18.
    Walter SD, Chao DL, Feuer W, Schiffman J, Char DH, Harbour JW (2016) Prognostic implications of tumor diameter in association with gene expression profile for uveal melanoma. JAMA ophthalmol 134:734–740CrossRefGoogle Scholar
  19. 19.
    Skinner CC, Augsburger JJ, Augsburger BD, Correa ZM (2017) Comparison of alternative tumor size classifications for posterior uveal melanomas. Invest Ophthalmol Vis Sci 58:3335–3342CrossRefGoogle Scholar
  20. 20.
    Gezgin G, Luk SJ, Cao J, Dogrusoz M, van der Steen DM et al (2017) PRAME as a potential target for immunotherapy in metastatic uveal melanoma. JAMA Ophthalmol 135:541–549CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Amy C. Schefler
    • 1
    • 2
    Email author
  • Emre Koca
    • 3
  • Eric H. Bernicker
    • 3
  • Zelia M. Correa
    • 4
    • 5
  1. 1.Retina Consultants of HoustonHoustonUSA
  2. 2.Blanton Eye InstituteHouston Methodist HospitalHoustonUSA
  3. 3.Cancer CenterHouston Methodist HospitalHoustonUSA
  4. 4.University of CincinnatiCincinnatiUSA
  5. 5.Wilmer Eye InstituteJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations