TY - JOUR
T1 - Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer
AU - Koestler, Devin C.
AU - Chalise, Prabhakar
AU - Cicek, Mine S.
AU - Cunningham, Julie M.
AU - Armasu, Sebastian
AU - Larson, Melissa C.
AU - Chien, Jeremy
AU - Block, Matthew
AU - Kalli, Kimberly R.
AU - Sellers, Thomas A.
AU - Fridley, Brooke L.
AU - Goode, Ellen L.
N1 - Funding Information:
The preparation of this manuscript, data collection and processing, and the analysis implemented in this examination was supported by the National Institute of Health grants, U19 CA148112 R01 CA122443 R01 CA114343.
PY - 2014/1/30
Y1 - 2014/1/30
N2 - 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.
AB - 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.
KW - Blood-based DNA methylation
KW - Integrative genomics
KW - Ovarian cancer
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U2 - 10.1186/1755-8794-7-8
DO - 10.1186/1755-8794-7-8
M3 - Article
C2 - 24479488
AN - SCOPUS:84893162063
SN - 1755-8794
VL - 7
JO - BMC medical genomics
JF - BMC medical genomics
IS - 1
M1 - 8
ER -