DNA hypomethylation and ovarian cancer biology.

Martin Widschwendter,Melanie Ehrlich,Hannes M MüLler,Elisabeth MüLler-Holzner,Heidi Fiegl,Guanchao Jiang,Peter W Laird,Alain G Zeimet,Georg Goebel,Christian Marth,Christian Woods

doi:10.1158/0008-5472.can-04-0238

Abstract

Hypomethylation of some portions of the genome and hypermethylation of others are very frequent in human cancer. The hypomethylation often involves satellite 2 (Sat2) DNA in the juxtacentromeric (centromere-adjacent) region of chromosome 1. In this study, we analyzed methylation in centromeric and juxtacentromeric satellite DNA in 115 ovarian cancers, 26 non-neoplastic ovarian specimens, and various normal somatic tissue standards. We found that hypomethylation of both types of satellite DNA in ovarian samples increased significantly from non-neoplastic toward cancer tissue. Furthermore, strong hypomethylation was significantly more prevalent in tumors of advanced stage or high grade. Importantly, extensive hypomethylation of Sat2 DNA in chromosome 1 was a highly significant marker of poor prognosis (relative risk for relapse, 4.1, and death, 9.4) and more informative than tumor grade or stage. Also, comparing methylation of satellite DNA and 15 5' gene regions, which are often hypermethylated in cancer or implicated in ovarian carcinogenesis, we generally found no positive or negative association between methylation changes in satellite DNA and in the gene regions. However, hypermethylation at two loci, CDH13 (at 16q24) and RNR1 (at 13p12), was correlated strongly with lower levels of Sat2 hypomethylation. The CDH13/Sat2 epigenetic correlation was seen also in breast cancers. We conclude that satellite DNA hypomethylation is an important issue in ovarian carcinogenesis as demonstrated by: (a) an increase from non-neoplastic tissue toward ovarian cancer; (b) an increase within the ovarian cancer group toward advanced grade and stage; and (c) the finding that strong hypomethylation was an independent marker of poor prognosis.

Highlights

In the United States and Europe, epithelial ovarian cancer causes more deaths than does cancer in any other female reproductive organ.It is estimated that there are ⬃25,400 new cases of ovarian cancer and14,300 deaths in the United States [1]
We conclude that satellite DNA hypomethylation is an important issue in ovarian carcinogenesis as demonstrated by: (a) an increase from nonneoplastic tissue toward ovarian cancer; (b) an increase within the ovarian cancer group toward advanced grade and stage; and (c) the finding that strong hypomethylation was an independent marker of poor prognosis
Ovarian cancers (115 specimens) from previously untreated patients and non-neoplastic ovarian tissue (26 specimens) from noncancer patients were analyzed for the extent of satellite DNA hypomethylation

Summary

Introduction

In the United States and Europe, epithelial ovarian cancer causes more deaths than does cancer in any other female reproductive organ.It is estimated that there are ⬃25,400 new cases of ovarian cancer and14,300 deaths in the United States [1]. In the United States and Europe, epithelial ovarian cancer causes more deaths than does cancer in any other female reproductive organ. It is estimated that there are ⬃25,400 new cases of ovarian cancer and. 14,300 deaths in the United States [1]. Because of the lack of early detection strategies, many ovarian cancer patients present with advanced stage disease, and the overall 5-year survival for these women is ⬍30% [2, 3]. The most important prognostic parameters for this disease are age, stage, grade, and optimal cytoreductive surgery (where all of the visible cancer in the peritoneal cavity is removed). There is a need for a better understanding of the molecular pathogenesis of ovarian cancer so that new drug targets or biomarkers that facilitate early detection can be identified

Methods

Results

Conclusion