Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

TY - JOUR

T1 - Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

AU - Yang, Yaohua

AU - Wu, Lang

AU - Shu, Xiang

AU - Lu, Yingchang

AU - Shu, Xiao-Ou

AU - Cai, Qiuyin

AU - Beeghly-Fadiel, Alicia

AU - Li, Bingshan

AU - Ye, Fei

AU - Berchuck, Andrew

AU - Anton-Culver, Hoda

AU - Banerjee, Susana

AU - Benitez, Javier

AU - Bjørge, Line

AU - Brenton, James D

AU - Butzow, Ralf

AU - Campbell, Ian G

AU - Chang-Claude, Jenny

AU - Chen, Kexin

AU - Cook, Linda S

AU - Cramer, Daniel W

AU - deFazio, Anna

AU - Dennis, Joe

AU - Doherty, Jennifer A

AU - Dörk, Thilo

AU - Eccles, Diana M

AU - Edwards, Digna Velez

AU - Fasching, Peter A

AU - Fortner, Renée T

AU - Gayther, Simon A

AU - Giles, Graham G

AU - Glasspool, Rosalind M

AU - Goode, Ellen L

AU - Goodman, Marc T

AU - Gronwald, Jacek

AU - Harris, Holly R

AU - Heitz, Florian

AU - Hildebrandt, Michelle A

AU - Høgdall, Estrid

AU - Høgdall, Claus K

AU - Huntsman, David G

AU - Kar, Siddhartha P

AU - Karlan, Beth Y

AU - Kelemen, Linda E

AU - Kiemeney, Lambertus A

AU - Kjaer, Susanne K

AU - Koushik, Anita

AU - Lambrechts, Diether

AU - Le, Nhu D

AU - Levine, Douglas A

AU - Massuger, Leon F

AU - Matsuo, Keitaro

AU - May, Taymaa

AU - McNeish, Iain A

AU - Menon, Usha

AU - Modugno, Francesmary

AU - Monteiro, Alvaro N

AU - Moorman, Patricia G

AU - Moysich, Kirsten B

AU - Ness, Roberta B

AU - Nevanlinna, Heli

AU - Olsson, Håkan

AU - Onland-Moret, N Charlotte

AU - Park, Sue K

AU - Paul, James

AU - Pearce, Celeste L

AU - Pejovic, Tanja

AU - Phelan, Catherine M

AU - Pike, Malcolm C

AU - Ramus, Susan J

AU - Riboli, Elio

AU - Rodriguez-Antona, Cristina

AU - Romieu, Isabelle

AU - Sandler, Dale P

AU - Schildkraut, Joellen M

AU - Setiawan, Veronica W

AU - Shan, Kang

AU - Siddiqui, Nadeem

AU - Sieh, Weiva

AU - Stampfer, Meir J

AU - Sutphen, Rebecca

AU - Swerdlow, Anthony J

AU - Szafron, Lukasz M

AU - Teo, Soo Hwang

AU - Tworoger, Shelley S

AU - Tyrer, Jonathan P

AU - Webb, Penelope M

AU - Wentzensen, Nicolas

AU - White, Emily

AU - Willett, Walter C

AU - Wolk, Alicja

AU - Woo, Yin Ling

AU - Wu, Anna H

AU - Yan, Li

AU - Yannoukakos, Drakoulis

AU - Chenevix-Trench, Georgia

AU - Sellers, Thomas A

AU - Pharoah, Paul D P

AU - Zheng, Wei

AU - Long, Jirong

N1 - ©2018 American Association for Cancer Research.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

AB - DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

KW - Biomarkers, Tumor/genetics

KW - Carcinoma, Ovarian Epithelial/genetics

KW - Cohort Studies

KW - DNA Methylation

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Models, Genetic

KW - Ovarian Neoplasms/genetics

KW - Predictive Value of Tests

KW - Risk

KW - Women's Health

U2 - 10.1158/0008-5472.CAN-18-2726

DO - 10.1158/0008-5472.CAN-18-2726

M3 - SCORING: Journal article

C2 - 30559148

VL - 79

SP - 505

EP - 517

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 3

ER -