title: DNA hypomethylation and ovarian cancer biology.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria. martin.widschwendter@uibk.ac.at
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Guanchao
authors.initials: G
authors.lastname: Jiang
authors.forename: Christian
authors.initials: C
authors.lastname: Woods
authors.forename: Hannes M
authors.initials: HM
authors.lastname: Müller
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.forename: Georg
authors.initials: G
authors.lastname: Goebel
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Müller-Holzner
authors.forename: Alain G
authors.initials: AG
authors.lastname: Zeimet
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Melanie
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D026924:Amino Acid Transport System A / Q000235:genetics; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis
chemical_list: D026924:Amino Acid Transport System A; D004273:DNA, Neoplasm; C498797:SLC38A2 protein, human