Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, SUNY Buffalo, Buffalo, New York 14263, USA.
Clin Cancer Res. 2011 Apr 15;17(8):2170-80. doi: 10.1158/1078-0432.CCR-10-2315. Epub 2011 Feb 4.
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.
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. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer.
CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat-α methylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival.
DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC.
在卵巢上皮癌（EOC）中，癌症种系（CG）抗原经常表达和低甲基化，但这种现象与整体 DNA 低甲基化的关系尚不清楚。此外，导致 DNA 低甲基化的潜在机制及其在 EOC 中的临床病理意义尚未确定。
我们使用定量 mRNA 表达和 DNA 甲基化分析来确定 X 连锁（MAGE-A1、NY-ESO-1、XAGE-1）和常染色体（BORIS、SOHLH2）CG 基因的表达和甲基化、整体 DNA 甲基化（5mdC 水平、LINE-1、Alu 和 Sat-α 甲基化）与 75 例 EOC 样本的临床病理之间的关系。此外，我们还研究了这些参数与许多被认为有助于癌症中 DNA 低甲基化的机制之间的关联。
CG 基因在 EOC 中协调表达，这与启动子 DNA 低甲基化有关。CG 启动子的低甲基化高度相关，与 LINE-1 和 Alu 甲基化密切相关，与 5mdC 水平中度相关，与 Sat-α 甲基化很少相关。BORIS 和 LINE-1 低甲基化以及 BORIS 表达与晚期有关。GADD45A 表达、MTHFR 基因型、DNMT3B 同工型表达和 BORIS mRNA 表达与甲基化参数无关。相反，BORIS/CTCF 表达比率与 DNA 低甲基化相关，并且与晚期和生存时间缩短相关。
在 EOC 中，DNA 低甲基化协调影响 CG 抗原基因启动子和特定的重复 DNA 元件，并与晚期疾病相关。BORIS/CTCF mRNA 表达比率与 DNA 低甲基化密切相关，并在 EOC 中预示不良预后。
