WT1 and WT1-AS genes are inactivated by promoter methylation in ovarian clear cell adenocarcinoma.
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.
Kaneuchi
Masanori
M
Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Sasaki
Masahiro
M
Tanaka
Yuichiro
Y
Shiina
Hiroaki
H
Yamada
Hideto
H
Yamamoto
Ritsu
R
Sakuragi
Noriaki
N
Enokida
Hideki
H
Verma
Mukesh
M
Dahiya
Rajvir
R
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics*; D018899:CpG Islands; D018284:Cystadenocarcinoma, Serous / Q000235:genetics*; D019175:DNA Methylation; D016373:DNA, Antisense / Q000378:metabolism*; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008957:Models, Genetic; D010051:Ovarian Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D025721:WT1 Proteins / Q000235:genetics*
D016373:DNA, Antisense; D025721:WT1 Proteins