Differential Genome-Wide DNA Methylation Patterns between Low Grade and High Grade Papillary Serous Carcinoma of the Ovary
A Ting, B Yang. Cleveland Clinic, Cleveland, OH
Background: It has been clear that low grade and high grade ovarian papillary serous carcinoma (PSC) have distinct pathologic features, clinical presentations and prognosis. A line of studies indicates that different genetic pathways exist between low grade and high grade PSC. However, epigenetic alterations, such as DNA methylation, between low grade and high grade PSC have not been well characterized. Utilizing MBD-isolated Genome Sequencing technique, we studied genome-wide DNA methylation patterns of low grade and high grade PSC.
Design: Twenty cases of stage IIIc ovarian PSC, including 10 cases of low grade PSC and 10 cases of high grade PSC, were included in the study. Genomic DNA was extracted from FFPE tissue. Genome-wide DNA methylation was characterized using Methy-CpG binding domain (MBD)-isolated genome sequencing (MiGS) technique.
Results: Among 27 millions of methylated sequences, we observed that globally, DNA methylation levels are similar in low grade and high grade PSC, with a slight increase of 5' promoter methylation observed in high grade PSC (3249 promoters in low grade vs. 3623 gene promoters in high grade). In addition to identifying the majority of reported promoter DNA methylation in the two groups, we detected differential methylation at over 1,000 loci between low grade and high grade PSC. These differential DNA methylation sites include RefSeq gene promoters, miRNAs, and intergenic sequences. Specifically, 306 genes are at least 10-fold hypermethylated in high grade PSC relative to low grade PSC. Only two genes show at least 10-fold hypomethylated in high grade than low grade PSC. Although chromosome 1 has, not surprisingly, the greatest number of differences because chromosome 1 is the largest chromosome in the genome, chromosome 19 harbored disproportional numbers of differences (55 genes out of 308 genes) between the two groups.
Conclusions: This is the first report of full genome-wide methylation sequencing between low grade and high grade PSC of the ovary. We found there were more than 300 gene promoters significantly hypermethylated in high grade than low grade PSC. Functional studies of these differential DNA methylation patterns could provide insights into the pathogenesis of ovarian PSC. Furthermore, these distinct methylation differences could be used as biomarkers to precisely distinguish, at a molecular level, between low grade and high grade PSC.
Category: Gynecologic & Obstetrics
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 151, Wednesday Afternoon