Histology-specific patterns of DNA methylation in Lynch-associated and sporadic ovarian cancer

Abstract 2964

 Epithelial ovarian cancer is a heterogeneous group of cancers, and molecular tools are urgently needed for a better understanding and targeted management of this often lethal disease. Since epigenetic methods can offer new tools for the management of ovarian cancer, our aim was to investigate epigenetic mechanisms in ovarian tumorigenesis representing different histological types. Expression profiling of ovarian and endometrial cancer cell lines treated with demethylating agents as well as literature were used to select gene candidates for epigenetic regulation. A methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay was constructed for thirteen genes to study methylation in 104 (85 sporadic and 19 Lynch syndrome-associated) ovarian carcinomas. 

Increased methylation (hypermethylation) was characteristic of ovarian cancer tissues relative to the corresponding normal tissues and hypermethylation was consistently more prominent in non-serous than serous tumors. The highest frequencies of hypermethylation were detected in Lynch-associated clear cell ovarian carcinomas.
An interesting finding among endometrioid ovarian carcinomas was a significant association of lower levels of methylation in HOXA9, RSK4 and SPARC with higher tumor grade; thus, the methylation patterns of high-grade endometrioid ovarian carcinomas resembled epigenetic characteristics of high-grade serous tumors. Overall, non-serous ovarian tumors of Lynch and sporadic origin (as opposed to serous tumors) showed frequent epigenetic inactivation in RSK4, SPARC, PROM1, HOXA10, HOXA9, WT1-AS, SFRP2, SFRP5, OPCML, and MIR34B.

Our findings provide important new information regarding some critical genes affected by epigenetic dysregulation in ovarian tumorigenesis. The results will be utilized in future experiments aiming to define the genetic and epigenetic origins of ovarian carcinomas of different types.