Epigenetic determinants of ovarian clear cell carcinoma biology
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 four 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. What's new? Ovarian cancer has several subtypes, and although different genetic mutations have been associated with particular subtypes, the molecular characteristics of ovarian clear cell carcinoma remain hazy. Aberrant DNA methylation can turn cells cancerous, and this study compared patterns of gene methylation in ovarian clear cell carcinomas, other ovarian cancer cells, and normal cells. They found that the clear cell carcinomas could indeed be identified by their distinctive pattern of DNA methylation. They found that this methylation pattern increased expression of certain stress response genes, while other genes, with tumor suppressive functions, were stifled. © 2013 UICC.
Yamaguchi, K; Huang, Z; Matsumura, N; Mandai, M; Okamoto, T; Baba, T; Konishi, I; Berchuck, A; Murphy, SK
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