WT1 and WT1-AS genes are inactivated by promoter methylation in ovarian clear cell adenocarcinoma

Authors

  • Masanori Kaneuchi M.D.,

    1. Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California
    2. Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan
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  • Masahiro Sasaki M.D.,

    1. Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California
    2. Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan
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  • Yuichiro Tanaka M.D.,

    1. Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California
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  • Hiroaki Shiina M.D.,

    1. Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California
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  • Hideto Yamada M.D.,

    1. Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan
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  • Ritsu Yamamoto M.D.,

    1. Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan
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  • Noriaki Sakuragi M.D.,

    1. Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan
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  • Hideki Enokida M.D.,

    1. Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California
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  • Mukesh Verma M.D.,

    1. Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland
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  • Rajvir Dahiya Ph.D., D.Sc.

    Corresponding author
    1. Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California
    • Urology Research Center (112F), University of California San Francisco and Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121
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    • Fax: (415) 750-6639


Abstract

BACKGROUND

Ovarian clear cell adenocarcinoma is associated with one of the poorest prognoses among human epithelial ovarian cancers. The authors hypothesized that Wilms tumor suppressor 1 gene (WT1) sense and antisense (WT1-AS) expression and their promoter methylation status could characterize ovarian clear cell adenocarcinoma from ovarian serous adenocarcinoma.

METHODS

To test this hypothesis, ovarian cancer cell lines and 42 cancer tissues (17 clear cell and 25 serous adenocarcinoma) were analyzed for expression and methylation of WT1 and WT1-AS genes.

RESULTS

These experiments demonstrated that all serous adenocarcinoma tissues expressed both WT1 and WT1-AS genes, although expression of these genes was lacking in clear cell adenocarcinoma. The WT1 and WT1-AS promoter were significantly methylated in clear cell adenocarcinoma (88.2% and 88.2%, respectively) compared with serous adenocarcinoma (24.0% and 20.0%, respectively). Significant correlation between methylation and mRNA expression status was observed for each gene. Also in agreement with these data, WT1 and WT1-AS negative ovarian cancer cell lines reexpressed these genes after treatment with the demethylating agent, 5-aza-2′-deoxycytidine.

CONCLUSIONS

The current study shows that CpG hypermethylation is an important mechanism of WT1 and WT1-AS gene inactivation in ovarian clear cell adenocarcinoma. This is the first report that has demonstrated differential expression and methylation of WT1-AS in ovarian clear cell and serous adenocarcinomas. This study presents new molecular characterizations between these two types of adenocarcinoma and may provide insight as to why clear cell adenocarcinoma has a poorer prognosis than serous adenocarcinoma of the ovary. Cancer 2005. © 2005 American Cancer Society.

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