Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome.
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.
Department of Biostatistics, University of Kansas, Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. bfridley@kumc.edu.
Brooke L
BL
Fridley
Sebastian M
SM
Armasu
Mine S
MS
Cicek
Melissa C
MC
Larson
Chen
C
Wang
Stacey J
SJ
Winham
Kimberly R
KR
Kalli
Devin C
DC
Koestler
David N
DN
Rider
Viji
V
Shridhar
Janet E
JE
Olson
Julie M
JM
Cunningham
Ellen L
EL
Goode
D000077216:Carcinoma, Ovarian Epithelial; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D025341:Principal Component Analysis; D016019:Survival Analysis; D016896:Treatment Outcome