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Open Access Research article

Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome

Brooke L Fridley1*, Sebastian M Armasu2, Mine S Cicek2, Melissa C Larson2, Chen Wang2, Stacey J Winham2, Kimberly R Kalli3, Devin C Koestler14, David N Rider2, Viji Shridhar5, Janet E Olson2, Julie M Cunningham5 and Ellen L Goode2

Author Affiliations

1 Department of Biostatistics, University of Kansas, Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA

2 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

3 Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

4 Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756, USA

5 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

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BMC Medical Genomics 2014, 7:21  doi:10.1186/1755-8794-7-21

Published: 28 April 2014

Abstract

Background

Genome-wide interrogation of DNA methylation (DNAm) in blood-derived leukocytes has become feasible with the advent of CpG genotyping arrays. In epithelial ovarian cancer (EOC), one report found substantial DNAm differences between cases and controls; however, many of these disease-associated CpGs were attributed to differences in white blood cell type distributions.

Methods

We examined blood-based DNAm in 336 EOC cases and 398 controls; we included only high-quality CpG loci that did not show evidence of association with white blood cell type distributions to evaluate association with case status and overall survival.

Results

Of 13,816 CpGs, no significant associations were observed with survival, although eight CpGs associated with survival at p < 10-3, including methylation within a CpG island located in the promoter region of GABRE (p = 5.38 x 10-5, HR = 0.95). In contrast, 53 CpG methylation sites were significantly associated with EOC risk (p <5 x10-6). The top association was observed for the methylation probe cg04834572 located approximately 315 kb upstream of DUSP13 (p = 1.6 x10-14). Other disease-associated CpGs included those near or within HHIP (cg14580567; p =5.6x10-11), HDAC3 (cg10414058; p = 6.3x10-12), and SCR (cg05498681; p = 4.8x10-7).

Conclusions

We have identified several CpGs in leukocytes that are differentially methylated by case-control status. Since a retrospective study design was used, we cannot differentiate whether DNAm was etiologic or resulting from EOC; thus, prospective studies of EOC-associated loci are the critical next step.

Keywords:
DNA methylation; CpG genotyping arrays; Epithelial ovarian cancer; Pathway; Etiology; Overall survival