Epigenetic determinants of ovarian clear cell carcinoma biology.
Epigenetic determinants of ovarian clear cell carcinoma biology.
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DOI：
10.1002/ijc.28701
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发表时间：
2014-08-01
影响因子：
6.4
通讯作者：
Murphy SK
中科院分区：
文献类型：
--
作者：
Yamaguchi K;Huang Z;Matsumura N;Mandai M;Okamoto T;Baba T;Konishi I;Berchuck A;Murphy SK
靶向方法揭示了卵巢癌中频繁的表观遗传学改变，但这些改变的范围和与疾病组织学亚型的关系尚不清楚。产生了14个透明细胞癌（CCC）、32个非CCC和4个相应的正常细胞系的全基因组甲基化和表达数据，以确定卵巢癌的不同组织学来源的细胞之间的甲基化谱如何不同。一致聚类表明CCC是表观遗传学上不同的。CCC中的表达和甲基化之间的反比关系被确定，表明甲基化的功能调节，包括22个低甲基化（UM）基因和276个高甲基化（HM）基因。分类和途径分析表明，CCC特异性UM基因参与应激反应，许多包含肝细胞核因子（HNF）1结合位点，而CCC特异性HM基因包括雌激素受体α（ER α）网络成员和参与肿瘤发展的基因。我们独立地验证了这些通路特异性基因中的17个的甲基化状态，并证实了相对于非CCC标本，CCC细胞系和原发性癌组织中HNF 1网络基因的表达增加和ER α通路基因的抑制。用去甲基化剂地西他滨处理三种CCC细胞系显著诱导了所有五种分析基因的表达。使用两个原发性卵巢癌数据集证实了途径表达的协调变化（两者p<0.0001）。我们的研究结果表明，甲基化调节CCC中的特定途径和生物学功能，低甲基化影响疾病的特征生物学，而高甲基化有助于致癌过程。
Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC, and 4 corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1 binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p<0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process.