PRAME expression and promoter hypomethylation in epithelial ovarian cancer

Wa Zhang, Carter J. Barger, Kevin H. Eng, David L Klinkebiel, Petra A. Link, Angela Omilian, Wiam Bshara, Kunle Odunsi, Adam R Karpf

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)45352-45369
Number of pages18
JournalOncotarget
Volume7
Issue number29
DOIs
StatePublished - Jan 1 2016

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DNA
Methyltransferases
Immunotherapy
Messenger RNA
Proteins
Ovarian epithelial cancer
Testicular Neoplasms
DNA Methylation
Methylation
Ovary
Cytoplasm
Biomarkers
Epithelial Cells
Immunohistochemistry
Antigens
Enzymes
Therapeutics

Keywords

  • Cancer testis antigens
  • DNA methylation
  • Epithelial ovarian cancer
  • High grade serous cancer
  • PRAME

ASJC Scopus subject areas

  • Oncology

Cite this

PRAME expression and promoter hypomethylation in epithelial ovarian cancer. / Zhang, Wa; Barger, Carter J.; Eng, Kevin H.; Klinkebiel, David L; Link, Petra A.; Omilian, Angela; Bshara, Wiam; Odunsi, Kunle; Karpf, Adam R.

In: Oncotarget, Vol. 7, No. 29, 01.01.2016, p. 45352-45369.

Research output: Contribution to journalArticle

Zhang, W, Barger, CJ, Eng, KH, Klinkebiel, DL, Link, PA, Omilian, A, Bshara, W, Odunsi, K & Karpf, AR 2016, 'PRAME expression and promoter hypomethylation in epithelial ovarian cancer', Oncotarget, vol. 7, no. 29, pp. 45352-45369. https://doi.org/10.18632/oncotarget.9977
Zhang, Wa ; Barger, Carter J. ; Eng, Kevin H. ; Klinkebiel, David L ; Link, Petra A. ; Omilian, Angela ; Bshara, Wiam ; Odunsi, Kunle ; Karpf, Adam R. / PRAME expression and promoter hypomethylation in epithelial ovarian cancer. In: Oncotarget. 2016 ; Vol. 7, No. 29. pp. 45352-45369.
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