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Published on: September 7, 2016
Epigenetic determinants of ovarian clear cell carcinoma biology
Ken Yamaguchi1, Zhiqing Huang, Noriomi Matsumura
1Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract:
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.
Insights
Clear cell ovarian cancer (CCC) exhibits distinct epigenetic profiles, with specific methylation patterns regulating key biological pathways. Hypomethylation influences CCC biology, while hypermethylation contributes to cancer development.
Area of Science:
- Genomics
- Epigenetics
- Oncology
Background:
- Epigenetic alterations are common in ovarian cancer, but their relationship to histologic subtypes remains unclear.
- Understanding subtype-specific epigenetic changes is crucial for targeted therapies.
Purpose of the Study:
- To investigate genome-wide methylation and expression profiles in clear cell carcinoma (CCC) and non-CCC ovarian cancer cell lines.
- To determine how methylation patterns differ between ovarian cancer histological subtypes.
- To identify functionally regulated genes and pathways affected by methylation in CCC.
Main Methods:
- Genome-wide methylation and expression profiling of 14 CCC, 32 non-CCC, and 4 normal ovarian cell lines.
- Consensus clustering to identify distinct epigenetic profiles.
- Analysis of gene expression and methylation relationships, including pathway and categorical analyses.
- Validation of methylation status and gene expression in cell lines and primary tissues.
- Treatment with a demethylating agent (Decitabine) to assess functional impact.
Main Results:
- CCC demonstrates a distinct epigenetic profile compared to non-CCC.
- Identified 22 hypomethylated (UM) and 276 hypermethylated (HM) genes in CCC, with inverse methylation-expression relationships.
- CCC-specific UM genes are involved in stress response and contain HNF1-binding sites.
- CCC-specific HM genes are linked to the estrogen receptor alpha (ERalpha) network and tumor development.
- Validated findings in cell lines and primary tissues, showing increased HNF1 network gene expression and repressed ERalpha pathway genes in CCC.
- Demethylating agent treatment induced expression of target genes in CCC cell lines.
Conclusions:
- DNA methylation plays a significant role in regulating specific pathways and biological functions in clear cell ovarian cancer.
- Hypomethylation contributes to the characteristic biology of CCC.
- Hypermethylation is implicated in the carcinogenic process of CCC.
- These findings highlight the potential for epigenetic-based therapeutic strategies in CCC.
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