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Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk

Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk
Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk
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.
0008-5472
505-517
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Long, Jirong
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Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao-ou, Cai, Qiuyin, Beeghly-fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D., Butzow, Ralf, Campbell, Ian G., Chang-claude, Jenny, Chen, Kexin, Cook, Linda S., Cramer, Daniel W., Defazio, Anna, Dennis, Joe, Doherty, Jennifer A., Dork, Thilo, Eccles, Diana M., Velez Edwards, Digna, Fasching, Peter A., Fortner, Renée T, Gayther, Simon A., Giles, Graham G., Glasspool, Rosalind M, Goode, Ellen L., Goodman, Marc T., Gronwald, Jacek, Harris, Holly R., Heitz, Florian, Hildebrandt, Michelle A.T., Høgdall, Estrid, Høgdall, Claus K., Huntsman, David G., Kar, Siddhartha P., Karlan, Beth Y., Kelemen, Linda E., Kiemeney, Lambertus A, Kjaer, Susanne K., Koushik, Anita, Lambrechts, Diether, Le, Nhu D., Levine, Douglas A., Massuger, Leon F.A.G., Matsuo, Keitaro, May, Taymaa, Mcneish, Iain A., Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N., Moorman, Patricia G., Moysich, Kirsten B., Ness, Roberta B., Nevanlinna, Heli, Olsson, Håkan, Onland-moret, N. Charlotte, Park, Sue K., Paul, James, Pearce, Celeste L., Pejovic, Tanja, Phelan, Catherine M., Pike, Malcolm C., Ramus, Susan J., Riboli, Elio, Rodríguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P., Schildkraut, Joellen M., Setiawan, Veronica W., Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J., Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz Michal, Teo, Soo Hwang, Tworoger, Shelley S., Tyrer, Jonathan P., Webb, Penelope M., Wentzensen, Nicolas, White, Emily, Willett, Walter C., Wolk, Alicja, Woo, Yin Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A., Pharoah, Paul D. P., Zheng, Wei and Long, Jirong (2019) Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk. Cancer Research, 79 (3), 505-517. (doi:10.1158/0008-5472.CAN-18-2726).

Record type: Article

Abstract

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.

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Accepted/In Press date: 6 December 2018
e-pub ahead of print date: 17 December 2018
Published date: February 2019

Identifiers

Local EPrints ID: 427112
URI: http://eprints.soton.ac.uk/id/eprint/427112
ISSN: 0008-5472
PURE UUID: 16a9a207-b905-4328-9e34-3b262f05b7a1
ORCID for Diana M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 03 Jan 2019 10:27
Last modified: 10 Jan 2022 05:05

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Contributors

Author: Yaohua Yang
Author: Lang Wu
Author: Xiang Shu
Author: Yingchang Lu
Author: Xiao-ou Shu
Author: Qiuyin Cai
Author: Alicia Beeghly-fadiel
Author: Bingshan Li
Author: Fei Ye
Author: Andrew Berchuck
Author: Hoda Anton-culver
Author: Susana Banerjee
Author: Javier Benitez
Author: Line Bjørge
Author: James D. Brenton
Author: Ralf Butzow
Author: Ian G. Campbell
Author: Jenny Chang-claude
Author: Kexin Chen
Author: Linda S. Cook
Author: Daniel W. Cramer
Author: Anna Defazio
Author: Joe Dennis
Author: Jennifer A. Doherty
Author: Thilo Dork
Author: Diana M. Eccles ORCID iD
Author: Digna Velez Edwards
Author: Peter A. Fasching
Author: Renée T Fortner
Author: Simon A. Gayther
Author: Graham G. Giles
Author: Rosalind M Glasspool
Author: Ellen L. Goode
Author: Marc T. Goodman
Author: Jacek Gronwald
Author: Holly R. Harris
Author: Florian Heitz
Author: Michelle A.T. Hildebrandt
Author: Estrid Høgdall
Author: Claus K. Høgdall
Author: David G. Huntsman
Author: Siddhartha P. Kar
Author: Beth Y. Karlan
Author: Linda E. Kelemen
Author: Lambertus A Kiemeney
Author: Susanne K. Kjaer
Author: Anita Koushik
Author: Diether Lambrechts
Author: Nhu D. Le
Author: Douglas A. Levine
Author: Leon F.A.G. Massuger
Author: Keitaro Matsuo
Author: Taymaa May
Author: Iain A. Mcneish
Author: Usha Menon
Author: Francesmary Modugno
Author: Alvaro N. Monteiro
Author: Patricia G. Moorman
Author: Kirsten B. Moysich
Author: Roberta B. Ness
Author: Heli Nevanlinna
Author: Håkan Olsson
Author: N. Charlotte Onland-moret
Author: Sue K. Park
Author: James Paul
Author: Celeste L. Pearce
Author: Tanja Pejovic
Author: Catherine M. Phelan
Author: Malcolm C. Pike
Author: Susan J. Ramus
Author: Elio Riboli
Author: Cristina Rodríguez-Antona
Author: Isabelle Romieu
Author: Dale P. Sandler
Author: Joellen M. Schildkraut
Author: Veronica W. Setiawan
Author: Kang Shan
Author: Nadeem Siddiqui
Author: Weiva Sieh
Author: Meir J. Stampfer
Author: Rebecca Sutphen
Author: Anthony J. Swerdlow
Author: Lukasz Michal Szafron
Author: Soo Hwang Teo
Author: Shelley S. Tworoger
Author: Jonathan P. Tyrer
Author: Penelope M. Webb
Author: Nicolas Wentzensen
Author: Emily White
Author: Walter C. Willett
Author: Alicja Wolk
Author: Yin Ling Woo
Author: Anna H. Wu
Author: Li Yan
Author: Drakoulis Yannoukakos
Author: Georgia Chenevix-Trench
Author: Thomas A. Sellers
Author: Paul D. P. Pharoah
Author: Wei Zheng
Author: Jirong Long

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