Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer.
BACKGROUND
Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk.


METHODS
We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). The Causal Inference Test (CIT) was implemented to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype.


RESULTS
Controlling for the estimated distribution of immune cells and other key covariates, our initial epigenome-wide association analysis revealed 1,993 significantly differentially methylated CpGs that between cases and controls (FDR, q < 0.05). The relationship between methylation and case-control status for these 1,993 CpGs was found to be highly consistent with the results of previously published, independent study that consisted of peripheral blood DNA methylation signatures in 131 pretreatment cases and 274 controls. Implementation of the CIT test revealed 17 CpG/SNP pairs, comprising 13 unique CpGs and 17 unique SNPs, which represent potential methylation-mediated relationships between genotype and EOC risk. Of these 13 CpGs, several are associated with immune related genes and genes that have been previously shown to exhibit altered expression in the context of cancer.


CONCLUSIONS
These findings provide additional insight into EOC etiology and may serve as novel biomarkers for EOC susceptibility.
Devin C
DC
Koestler
Prabhakar
P
Chalise
Mine S
MS
Cicek
Julie M
JM
Cunningham
Sebastian
S
Armasu
Melissa C
MC
Larson
Jeremy
J
Chien
Matthew
M
Block
Kimberly R
KR
Kalli
Thomas A
TA
Sellers
Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. bfridley@kumc.edu.
Brooke L
BL
Fridley
Ellen L
EL
Goode
D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics