title: Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.forename: Shingo
authors.initials: S
authors.lastname: Fujii
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016212:Transforming Growth Factor beta