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Epigenetic determinants of ovarian clear cell carcinoma biology.

Publication ,  Journal Article
Yamaguchi, K; Huang, Z; Matsumura, N; Mandai, M; Okamoto, T; Baba, T; Konishi, I; Berchuck, A; Murphy, SK
Published in: Int J Cancer
August 1, 2014

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.

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Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

August 1, 2014

Volume

135

Issue

3

Start / End Page

585 / 597

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Real-Time Polymerase Chain Reaction
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Humans
  • Hepatocyte Nuclear Factor 1
  • Female
  • Epigenomics
  • DNA Methylation
 

Citation

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Yamaguchi, K., Huang, Z., Matsumura, N., Mandai, M., Okamoto, T., Baba, T., … Murphy, S. K. (2014). Epigenetic determinants of ovarian clear cell carcinoma biology. Int J Cancer, 135(3), 585–597. https://doi.org/10.1002/ijc.28701
Yamaguchi, Ken, Zhiqing Huang, Noriomi Matsumura, Masaki Mandai, Takako Okamoto, Tsukasa Baba, Ikuo Konishi, Andrew Berchuck, and Susan K. Murphy. “Epigenetic determinants of ovarian clear cell carcinoma biology.Int J Cancer 135, no. 3 (August 1, 2014): 585–97. https://doi.org/10.1002/ijc.28701.
Yamaguchi K, Huang Z, Matsumura N, Mandai M, Okamoto T, Baba T, et al. Epigenetic determinants of ovarian clear cell carcinoma biology. Int J Cancer. 2014 Aug 1;135(3):585–97.
Yamaguchi, Ken, et al. “Epigenetic determinants of ovarian clear cell carcinoma biology.Int J Cancer, vol. 135, no. 3, Aug. 2014, pp. 585–97. Pubmed, doi:10.1002/ijc.28701.
Yamaguchi K, Huang Z, Matsumura N, Mandai M, Okamoto T, Baba T, Konishi I, Berchuck A, Murphy SK. Epigenetic determinants of ovarian clear cell carcinoma biology. Int J Cancer. 2014 Aug 1;135(3):585–597.
Journal cover image

Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

August 1, 2014

Volume

135

Issue

3

Start / End Page

585 / 597

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Real-Time Polymerase Chain Reaction
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Humans
  • Hepatocyte Nuclear Factor 1
  • Female
  • Epigenomics
  • DNA Methylation