PRAME expression and promoter hypomethylation in epithelial ovarian cancer.

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.

DNA hypomethylation-mediated activation of Cancer/Testis Antigen 45 (CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a highly lethal malignancy due to a lack of early detection approaches coupled with poor outcomes for patients with clinically advanced disease. Cancer-testis (CT) or cancer-germline genes encode antigens known to generate spontaneous anti-tumor immunity in cancer patients. CT45 genes are a recently discovered 6-member family of X-linked CT genes with oncogenic function.

BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer.

Cancer germline (CG) genes are normally expressed in germ cells and aberrantly expressed in a variety of cancers; their immunogenicity has led to the widespread development of cancer vaccines targeting these antigens. BORIS/CTCFL is an autosomal CG antigen and promising cancer vaccine target. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation.

Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis.

The drivers of abnormal DNA methylation in human cancers include widespread aberrant splicing of the DNMT3B gene, producing abnormal transcripts that encode truncated proteins that may act as dominant negative isoforms. To test whether reduced Dnmt3b dosage can alter tumorigenesis, we bred Dnmt3b(+/-) mice to Eµ-Myc mice, a mouse model susceptible to B-cell lymphomas. Eµ-Myc/Dnmt3b(+/-) mice showed a dramatic acceleration of lymphomagenesis, greater even than that observed in Eµ-Myc mice that express a truncated DNMT3B isoform found in human tumors, DNMT3B7.

Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: association with the BORIS/CTCF expression ratio and advanced stage.

Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined.

Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples.

Association between global DNA hypomethylation in leukocytes and risk of breast cancer.

Background: Global DNA hypomethylation may result in chromosomal instability and oncogene activation, and as a surrogate of systemic methylation activity, may be associated with breast cancer risk.

Methods: Samples and data were obtained from women with incident early-stage breast cancer (I-IIIa) and women who were cancer free, frequency matched on age and race. In preliminary analyses, genomic methylation of leukocyte DNA was determined by measuring 5-methyldeoxycytosine (5-mdC), as well as methylation analysis of the LINE-1-repetitive DNA element.

Distinct roles for histone methyltransferases G9a and GLP in cancer germ-line antigen gene regulation in human cancer cells and murine embryonic stem cells.

The H3K9me2 histone methyltransferases G9a and GLP repress Mage-a class cancer germ-line (CG) antigen gene expression in murine embryonic stem (ES) cells, but the role of these enzymes in CG antigen gene regulation in human cancer cells is unknown. Here we show that whereas independent or dual knockdown of G9a and GLP in human cancer cells leads to reduced global and CG antigen promoter-associated H3K9me2 levels, it does not activate CG antigen gene expression. Moreover, CG antigen gene repression is maintained following pharmacologic targeting of G9a or treatment of G9a knockdown cells with the histone deacetylase inhibitor trichostatin A.

p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia.

While the therapeutic activity of the deoxycytidine analogue decitabine is thought to reflect its ability to reactivate methylation-silenced genes, this agent is also known to trigger p53-dependent DNA damage responses. Here, we report that p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a robust transcriptional target of decitabine. In cancer cells, decitabine treatment induces p53R2 mRNA expression, protein expression, and promoter activity in a p53-dependent manner.

DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer.

Brother of the Regulator of Imprinted Sites (BORIS/CTCFL) is an autosomal cancer germline (CG) or cancer-testis antigen gene and paralog of CTCF that has been proposed to function as an oncogene in human cancer via dysregulation of the cancer epigenome. Here we show that genetic disruption of DNA methylation in human cancer cells induces BORIS expression, coincident with DNA hypomethylation and an altered histone H3 modification pattern at the BORIS promoter. Rapid amplification of cDNA ends (RACE) mapping revealed that the transcriptional start site of BORIS in human testis, DNMT deficient human cancer cells, and human epithelial ovarian cancer (EOC) tissues, is similar and lies within the 5' CpG island.