International data indicates that ovarian cancer is the leading cause of death among gynecological cancers.
To better understand the disease and improve therapies, researchers are investigating how deregulation of genes across the genome could be contributing to malignancy. In a study published online today in Genome Research
), scientists have identified age-related gene-specific accumulation of DNA methylation that suppresses a critical cellular pathway contributing to ovarian carcinogenesis, information that will be crucial for future translational research.
Epigenetic silencing of genes by a chemical modification called DNA methylation is known to play a role in the development of malignancies such as ovarian cancer by turning off genes that normally suppress tumor growth. Yet the scope of DNA methylation across the entire cancer genome is not well understood, hindering efforts to understand the biological basis of the disease.
In this study, an international team of researchers from the United States and Japan performed a genome-wide analysis of gene expression in ovarian cancer by transcriptome profiling, looking for genes silenced by DNA methylation that might be involved in the disease. The research group analyzed gene expression in established ovarian cancer cell lines and primary cultured ovarian cancer cells that were either mock treated, or treated with a chemical agent that blocks DNA methylation.
This strategy identified 378 candidate methylated genes in ovarian cancers. When the group began investigating the functions of the genes subject to methylation in the malignancies, an intriguing clue to the biology of ovarian cancer arose from the list.
"While we hoped to identify a substantial group of candidate methylated genes," said researcher Susan Murphy of Duke University Medical Center and senior author of the study, "we did not anticipate that we would find methylation-mediated deregulation of many genes involved in a specific functional pathway, the TGF-beta pathway."
The TGF-beta pathway is a cellular signaling network that controls cell growth and differentiation, normally curbing tumor growth, but can promote cancer when disrupted. This work reports for the first time that methylation of genes in the TGF-beta superfamily suppresses the TGF-beta pathway in ovarian cancer. Murphy and colleagues also observed that methylation increased with patient age, suggesting that gene-specific methylation accumulates over time.
Murphy added that the methylated genes identified in this study will aid in the design of new strategies to treat the disease. "Knowing the identity of these genes provides for the ability to carry out focused studies to understand their specific role in ovarian cancer," Murphy explained, "and may present opportunities for targeted therapeutic interventions."