Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
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Class 1 tumors were more likely to be PRAME-, whereas Class 2 tumors were more likely to be PRAME.
In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations and inversely associated with EIF1AX mutations.
PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter.
Analyses were performed on 555 de-identified samples from Castle Biosciences, 123 samples from our center, and 80 samples from the TCGA. PRAME is aberrantly hypomethylated and activated in Class 1 and Class 2 uveal melanomas and is associated with increased metastatic risk in both classes.
Tumors with the Class 1 profile have a low metastatic risk, whereas those with the Class 2 profile have a high metastatic risk.
While the vast majority of metastatic events in uveal melanoma arise from Class 2 tumors, a small subset of Class 1 tumors also give rise to metastasis.
Class 1 tumors with low expression of these genes and very low predicted metastatic risk were called Class "1A," whereas those with high expression and higher predicted metastatic risk were called Class "1B."" In our efforts to further improve the prognostic accuracy of the gene array platform, we conducted a genome wide search for new biomarkers and found that mRNA expression of the cancer-testis antigen Preferentially Expressed Antigen in Melanoma was an accurate biomarker for metastasis in Class 1 tumors.
Figure 5: Transcriptional activation of PRAME is associated with hypomethylation of the PRAME promoter in uveal melanoma." />
Figure 5: Transcriptional activation of PRAME is associated with hypomethylation of the PRAME promoter in uveal melanoma. (A) The only normal adult human tissue that expresses high levels of PRAME mRNA is testis. Data were obtained through the GTEx Portal [41]. (B) Locations of 12 CpG sites (blue bars) within or near the PRAME promoter that exhibited significantly decreased methylation in PRAME+ uveal melanomas (n = 41) compared to PRAME- samples (n = 39) at a significance level of FDR < 0.05. (C) Scatter plots showing the relationship between PRAME mRNA expression levels (obtained from TCGA RNA-Seq data) and PRAME promoter methylation (obtained from TCGA Infinium HumanMethylation450 BeadChip data) using two representative methylation probes (cg17648213 and cg27303185). Spearman's rank correlation coefficient was used to determine P-values. Graphs depicting the other 10 differentially methylated probes are in Supplementary Figure S1. (D) Methylation data for the cg27303185 methylation probe was plotted for normal tissues obtained from Marmal-aid [40]. A separate panel (right) depicts PRAME+ and PRAME- uveal melanomas samples for comparison. RPKM, reads per kilobase of transcript per million mapped reads; CPM, counts per million.
The purpose of the present Oncotarget study was to study PRAME expression in a much larger number of Class 1 and, for the first time, in Class 2 uveal melanomas spanning the true range of tumor sizes encountered in clinical practice.
The present Oncotarget study was to study PRAME expression in a much larger number of Class 1 and, for the first time, in Class 2 uveal melanomas
We sought to define a threshold value for calling a tumor sample positive for PRAME expression, compare PRAME expression to the 1A/1B designation in Class 1 tumors, identify clinical and molecular factors associated with PRAME expression, evaluate the prognostic value of PRAME expression in Class 2 tumors, and determine whether PRAME expression in uveal melanoma is correlated with promoter hypomethylation.
The Harbour Research Team concluded in their OncotargetResearch Paper that we have provided a threshold for PRAME expression from qPCR data for primary uveal melanomas across a wide spectrum of tumor sizes and in both tumor classes representative of actual clinical practice.
We previously identified PRAME expression as a biomarker for increased metastatic risk in Class 1 tumors, and here we showed for the first time that PRAME expression is also associated with worse prognosis among Class 2 tumors.
We demonstrated that specific chromosomal gains and losses, as well as specific driver mutations, are found preferentially in PRAME tumors.
Finally, we showed that specific CpG sites around the PRAME promoter are differentially hypomethylated in PRAME tumors, suggesting that the aberrant transcriptional activation of PRAME in uveal melanoma is the result of epigenetic reprogramming during tumor progression.
In addition to its prognostic value, PRAME expression status may potentially be useful in the future for guiding the use of PRAME-directed immunotherapy, which would make PRAME the first true "companion prognostic" biomarker in uveal melanoma.
Figure 5: Transcriptional activation of PRAME is associated with hypomethylation of the PRAME promoter in uveal melanoma." />