|
|
|
|
|
|
|
|
open access
Abstract
Diagnosis
and treatment of epithelial ovarian cancer is challenging due to the
poor understanding of the pathogenesis of the disease. Our aim was to
investigate epigenetic mechanisms in ovarian tumorigenesis and,
especially, whether tumors with different histological subtypes or
hereditary background (Lynch syndrome) exhibit differential
susceptibility to epigenetic inactivation of growth regulatory genes.
Gene candidates for epigenetic regulation were identified from the
literature and by expression profiling of ovarian and endometrial cancer
cell lines treated with demethylating agents. Thirteen genes were
chosen for methylation-specific multiplex ligation-dependent probe
amplification assays on 104 (85 sporadic and 19 Lynch
syndrome-associated) ovarian carcinomas. Increased methylation (i.e.,
hypermethylation) of variable degree was characteristic of ovarian
carcinomas relative to the corresponding normal tissues, and
hypermethylation was consistently more prominent in non-serous than
serous tumors for individual genes and gene sets investigated. Lynch
syndrome-associated clear cell carcinomas showed the highest frequencies
of hypermethylation. Among endometrioid ovarian carcinomas, lower
levels of promoter methylation of RSK4, SPARC, and HOXA9 were significantly associated with higher tumor grade; thus, the
methylation patterns showed a shift to the direction of high-grade
serous tumors.
In conclusion, we provide evidence of a frequent
epigenetic inactivation of RSK4, SPARC, PROM1, HOXA10, HOXA9, WT1-AS, SFRP2, SFRP5, OPCML,
and MIR34B in the development of non-serous ovarian carcinomas of Lynch
and sporadic origin, as compared to serous tumors. Our findings shed
light on the role of epigenetic mechanisms in ovarian tumorigenesis and
identify potential targets for translational applications.
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.