PRAME: Potential Role in Uveal Melanoma
PRAME (preferentially expressed antigen in melanoma) is a cancer test for an antigen gene that is not expressed at appreciable levels in normal adult tissues, but its expression can become aberrantly increased in some types of cancer, including sarcoma, hematological malignancies, breast cancer, and melanoma. While the exact mechanism of PRAME in these cancers is under investigation, PRAME can repress retinoic acid signaling and thus affect proliferation, differentiation, and apoptosis. Once expressed, the PRAME protein can be processed and presented on the surface of cells, thereby serving as a potential target for therapeutic intervention. There are PRAME-directed therapies being tested in clinical trials for multiple cancer types.
PRAME in Class 1 and 2 Uveal Melanoma Tumors
While the risk for Class 1 patients has been shown to be consistently low across multiple studies, a small proportion of Class 1 tumors do metastasize. The Class 1 sub-classification makes use of 2 genes within the DecisionDx-UM gene set to identify the lowest-risk Class 1 patients (Class 1A) and those that may have a slightly higher risk of metastasis (Class 1B).
More recently, as published in Clinical Cancer Research, Dr. J. William Harbour, of Bascom Palmer Eye Institute, and colleagues expanded from using just the 15 genes in the DecisionDx-UM assay to sub-classify Class 1 tumors that do and do not metastasize to using whole transcriptomic analysis. Using this approach, PRAME was identified as the most significantly different gene between these Class 1 tumors. A threshold expression level for determining whether a tumor was PRAME positive or negative was determined.
Additional results of this study were:
- In 64 Class 1 patients with known clinical outcomes, none of the PRAME-negative tumors metastasized, while the 7 Class 1 tumors that metastasized were all PRAME positive.
- PRAME expression was strongly correlated with metastasis (p=0.006 by log-rank test).
- This association of PRAME positivity with metastasis in low-risk (Class 1 or disomy 3) tumors was also demonstrated in 3 additional public microarray datasets.
- All Class 1 tumors that metastasized and had DecisionDx-UM sub-classification were also Class 1B.
In the second study of PRAME, published in Oncotarget, Dr. Harbour and colleagues used PRAME gene expression data from 678 uveal melanoma tumors from multiple institutions to refine the threshold that determines PRAME positivity/negativity. This threshold has now been validated in 958 uveal melanoma tumors. The study also examined PRAME in Class 2 tumors, correlations of PRAME with chromosomal aberrations, and PRAME association with DNA mutations.
The results suggested:
- Class 2 tumors that are PRAME positive have a shorter time to metastasis compared to Class 2/PRAME-negative tumors.
- PRAME positivity in Class 1 and 2 tumors was not significantly correlated with monosomy 3.
- PRAME positivity was associated with SF3B1 mutations and inversely correlated with EIF1AX mutations in Class 1 tumors.
- PRAME positivity was associated with BAP1 mutations, likely because BAP1 mutations are most prevalent in Class 2 patients.
Although the exact clinical implications of PRAME are still under investigation and will be prospectively evaluated in an upcoming multicenter trial led by Dr. Harbour, PRAME has the potential to be important for more precise risk assessment and therapeutic options. Given the lack of residual biopsy tissue after DecisionDx-UM testing, Castle Biosciences is offering PRAME testing as an optional add-on test to the DecisionDx-UM test. The ordering physician must indicate on the DecisionDx-UM test order form that they want to order DecisionDx-PRAME.
It is important that the interpretation of PRAME only be done in the context of a DecisionDx-UM result. A PRAME-positive result may indicate an increase in metastatic risk for a Class 1 uveal melanoma and a shorter time to metastasis for a Class 2 uveal melanoma. Specific risk estimates associated with PRAME positivity have not yet been determined, pending additional clinical validation. If a tumor is negative for PRAME, the prognosis indicated by the DecisionDx-UM Class is not expected to be altered.
DecisionDx-PRAME can be ordered in conjunction with DecisionDx-UM by electing to do PRAME testing on the DecisionDx-UM order form.