Abstract
PRAME is a cancer-testis antigen (CTA) and potential immuno-therapeutic target, but has not been well-studied in epithelial ovarian cancer (EOC) or its high grade serous (HGSC) subtype. Compared to normal ovary, PRAME expression was significantly increased most EOC, regardless of stage and grade. Interestingly, PRAME mRNA expression was associated with improved survival in the HGSC subtype. The PRAME locus was a frequent target for copy number alterations (CNA) in HGSC but most changes were heterozygous losses, indicating that elevated PRAME expression is not typically due to CNA. In contrast, PRAME promoter DNA hypomethylation was very common in EOC and HGSC and correlated with increased PRAME expression. PRAME expression and promoter hypomethylation both correlated with LINE-1 hypomethylation, a biomarker of global DNA hypomethylation. Pharmacologic or genetic disruption of DNA methyltransferase (DNMT) enzymes activated PRAME expression in EOC cells. Immunohistochemistry (IHC) of PRAME in EOC revealed frequent, but low level, protein expression, and expression was confined to epithelial cells and localized to the cytoplasm. Cytoplasmic PRAME expression was positively associated with PRAME mRNA expression and negatively associated with promoter methylation, but the latter correlation was not statistically significant. PRAME protein expression did not correlate with EOC clinicopathology or survival. In summary, PRAME is frequently expressed in EOC at the mRNA and protein levels, and DNA methylation is a key mechanism regulating its expression. These data support PRAME as an immunotherapy target in EOC, and suggest treatment with DNMT inhibitors as a means to augment PRAME immunotherapy.
Highlights
Ovarian cancer is the seventh most common female cancer worldwide and accounts for the fifth most female cancer deaths in the US [1, 2]
We show here that the cancer-testis antigen (CTA) PRAME is frequently expressed in epithelial ovarian cancer (EOC) and High grade serous cancer (HGSC) at the mRNA and protein levels, and demonstrate that promoter DNA
PRAME expression and promoter hypomethylation were associated with LINE-1 hypomethylation, suggesting that the global hypomethylation phenotype often observed in EOC is connected to PRAME regulation, analogous to other CTA genes [13, 41, 42, 51, 52]
Summary
Ovarian cancer is the seventh most common female cancer worldwide and accounts for the fifth most female cancer deaths in the US [1, 2]. 90% of ovarian cancer cases are epithelial (EOC) [3]. More than 60% of EOC are diagnosed with advanced disease, and the five-year survival for these women is < 30% [2]. High grade serous cancer (HGSC) is the most common EOC subtype, accounting for ~70% of cases. HGSC is often www.impactjournals.com/oncotarget clinically-advanced (stage 3+), is high grade (grade 2+), and is associated with poor survival [4]. Recent largescale genomic studies have shed light on the molecular mechanisms of HGSC [4, 5]. Continued investigations are needed to facilitate improved diagnostic and therapeutic approaches
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