RT Journal
A1 Matsumura, Noriomi
A1 Huang, Zhiqing
A1 Mori, Seiichi
A1 Baba, Tsukasa
A1 Fujii, Shingo
A1 Konishi, Ikuo
A1 Iversen, Edwin S.
A1 Berchuck, Andrew
A1 Murphy, Susan K.
T1 Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer
JF Genome Research 
JO Genome Research 
YR 2011 
FD January 01 
VO 21 
IS 1 
SP 74 
OP 82 
DO 10.1101/gr.108803.110 
UL http://genome.cshlp.org/content/21/1/74.abstract 
AB Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis.