Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Genome Res. 2011 Jan;21(1):74-82. doi: 10.1101/gr.108803.110. Epub 2010 Dec 14.
Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis.
上皮性卵巢癌是妇科恶性肿瘤死亡的主要原因。诊断通常发生在转移扩散后，这主要反映了早期疾病的模糊症状，加上缺乏有效的筛查策略。基因调控的表观遗传机制，包括 DNA 甲基化，是正常细胞功能的基础，在肿瘤发生中也起着重要作用。为了阐明 DNA 甲基化在卵巢癌中的生物学和临床相关性，我们对 39 种细胞系和 17 种原代培养标本进行了表达微阵列分析，这些标本在存在或不存在 DNA 甲基转移酶 (DNMT) 抑制剂的情况下生长。两个参数，诱导表达和未处理样品的标准差，确定了 378 个候选甲基化基因，其中许多与 TGF-β 信号通路相关。我们分析了其中的 43 个基因，它们都显示出甲基化。DNMT 抑制剂的处理增加了 TGF-β 通路的活性。使用这 378 个基因对卵巢癌进行层次聚类，可重现性地产生一个与 TGF-β 通路活性密切相关的独特基因簇，该基因簇可根据年龄区分患者。这些数据表明，与年龄相关的表观遗传修饰的积累导致 TGF-β 信号通路的抑制，并促进卵巢癌的发生。
