Abstract
Abstract Background: Ovarian cancer is the gynecological disease with the highest death rate. Efforts towards ovarian cancer research are needed to develop early detection tools, better therapies, cures and to prevent the disease. DNA methylation profiling of a large set of putative cancer biomarkers may help to identify relevant biological aspects of ovarian cancer. Materials and Methods: We selected 106 patients diagnosed for ovarian cancer (35 serous, 30 endometrioid, 32 mucinous and 8 germinal tumors) for which clinicopathological informations were available and 17 histologically normal ovarian tissues as control. In order to identify methylation signatures, a method called Methylation Ligation-dependant Macroarray (MLM) and developed in our laboratory was applied to DNA extracted from microdissected formalin-fixed and paraffin-embedded tissue sections. The MLM technology, derived from a multiplex ligation assay coupled with an array-based analysis of uniform size amplification products, permits the methylation status analysis of 60 promoter regions at the same time. Results: Each of the 106 ovarian tumor samples analyzed had a unique methylation profile. Hierarchical clustering identified mainly two groups of patients with distinct methylation profiles. The first group of tumors contained low levels of methylation, whereas the second group had higher methylation levels. The group 1 included normal ovarian tissues as well as a large number of ovarian serous tumors. Endometrioid and mucinous tumors were more represented in the group 2. When looking at the gene level, the highest methylation frequency was detected in the TAC1, SPARC, ADAMTS12 and hTERT promoter genes. The promoter of the BORIS/CTCFL cancer testis-antigen gene was found hypomethylated in several tumors, mainly in serous and germinal types. Located in the X-chromosome, the DAX1 promoter gene, which is partially methylated in normal ovarian tissues, was found hypomethylated or hypermethylated in tumors. Interestingly, the difference between the hypo- and hyper-methylated groups concerned mainly genes belonging to the WNT pathway. Conclusion: The marked differences in methylation profiles independently of histological subtypes underscore the importance of characterizing tumors at the molecular level. Further investigations are needed to evaluate the role of the WNT signaling pathway as a marker and putative target for cisplatin chemosensitivity in ovarian tumors. Citation Format: Sonia T. Chelbi, Lorena Losi, Sara Saponaro, Patricia Martin, Richard Braunschweig, Jean Benhattar. DNA methylation profiling of ovarian tumors by methylation ligation-dependant macroarray. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4254. doi:10.1158/1538-7445.AM2013-4254
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