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

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

doi:10.1158/0008-5472.CAN-18-2726

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

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

Quantitative Health Sciences

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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 ¼ 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, ARH-GAP27, 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.

Original language	English (US)
Pages (from-to)	505-517
Number of pages	13
Journal	Cancer research
Volume	79
Issue number	3
DOIs	https://doi.org/10.1158/0008-5472.CAN-18-2726
State	Published - Feb 1 2019

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-18-2726

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Yang, Y., Wu, L., Shu, X., Lu, Y., Shu, X. O., Cai, Q., Beeghly-Fadiel, A., Li, B., Ye, F., Berchuck, A., Anton-Culver, H., Banerjee, S., Benitez, J., Bjørge, L., Brenton, J. D., Butzow, R., Campbell, I. G., Chang-Claude, J., Chen, K., ... Long, J. (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. https://doi.org/10.1158/0008-5472.CAN-18-2726

Yang, Y, Wu, L, Shu, X, Lu, Y, Shu, XO, Cai, Q, Beeghly-Fadiel, A, Li, B, Ye, F, Berchuck, A, Anton-Culver, H, Banerjee, S, Benitez, J, Bjørge, L, Brenton, JD, Butzow, R, Campbell, IG, Chang-Claude, J, Chen, K, Cook, LS, Cramer, DW, De Fazio, A, Dennis, J, Doherty, JA, Eccles, DM, Edwards, DV, Fasching, PA, Fortner, RT, Gayther, SA, Giles, GG, Glasspool, RM, Goode, EL, Goodman, MT, Gronwald, J, Harris, HR, Heitz, F, Hildebrandt, MA, Høgdall, E, Høgdall, CK, Huntsman, DG, Kar, SP, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Koushik, A, Lambrechts, D, Le, ND, Levine, DA, Massuger, LF, Matsuo, K, May, T, McNeish, IA, Menon, U, Modugno, F, Monteiro, AN, Moorman, PG, Moysich, KB, Ness, RB, Nevanlinna, H, Olsson, H, Charlotte Onland-Moret, N, Park, SK, Paul, J, Pearce, CL, Pejovic, T, Phelan, CM, Pike, MC, Ramus, SJ, Riboli, E, Rodriguez-Antona, C, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Shan, K, Siddiqui, N, Sieh, W, Stampfer, MJ, Sutphen, R, Swerdlow, AJ, Szafron, LM, Teo, SH, Tworoger, SS, Tyrer, JP, Webb, PM, Wentzensen, N, White, E, Willett, WC, Wolk, A, Woo, YL, Wu, AH, Yan, L, Yannoukakos, D, Chenevix-Trench, G, Sellers, TA, Pharoah, PDP, Zheng, W & Long, J 2019, 'Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk', Cancer research, vol. 79, no. 3, pp. 505-517. https://doi.org/10.1158/0008-5472.CAN-18-2726

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

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 ¼ 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, ARH-GAP27, 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.",

author = "Yaohua Yang and Lang Wu and Xiang Shu and Yingchang Lu and Shu, {Xiao Ou} and Qiuyin Cai and Alicia Beeghly-Fadiel and Bingshan Li and Fei Ye and Andrew Berchuck and Hoda Anton-Culver and Susana Banerjee and Javier Benitez and Line Bj{\o}rge and Brenton, {James D.} and Ralf Butzow and Campbell, {Ian G.} and Jenny Chang-Claude and Kexin Chen and Cook, {Linda S.} and Cramer, {Daniel W.} and {De Fazio}, Anna and Joe Dennis and Doherty, {Jennifer A.} and Eccles, {Diana M.} and Edwards, {Digna Velez} and Fasching, {Peter A.} and Fortner, {Rene{\'e} T.} and Gayther, {Simon A.} and Giles, {Graham G.} and Glasspool, {Rosalind M.} and Goode, {Ellen L.} and Goodman, {Marc T.} and Jacek Gronwald and Harris, {Holly R.} and Florian Heitz and Hildebrandt, {Michelle A.} and Estrid H{\o}gdall and H{\o}gdall, {Claus K.} and Huntsman, {David G.} and Kar, {Siddhartha P.} and Karlan, {Beth Y.} and Kelemen, {Linda E.} and Kiemeney, {Lambertus A.} and Kjaer, {Susanne K.} and Anita Koushik and Diether Lambrechts and Le, {Nhu D.} and Levine, {Douglas A.} and Massuger, {Leon F.} and Keitaro Matsuo and Taymaa May and McNeish, {Iain A.} and Usha Menon and Francesmary Modugno and Monteiro, {Alvaro N.} and Moorman, {Patricia G.} and Moysich, {Kirsten B.} and Ness, {Roberta B.} and Heli Nevanlinna and H{\aa}kan Olsson and {Charlotte Onland-Moret}, N. and Park, {Sue K.} and James Paul and Pearce, {Celeste L.} and Tanja Pejovic and Phelan, {Catherine M.} and Pike, {Malcolm C.} and Ramus, {Susan J.} and Elio Riboli and Cristina Rodriguez-Antona and Isabelle Romieu and Sandler, {Dale P.} and Schildkraut, {Joellen M.} and Setiawan, {Veronica W.} and Kang Shan and Nadeem Siddiqui and Weiva Sieh and Stampfer, {Meir J.} and Rebecca Sutphen and Swerdlow, {Anthony J.} and Szafron, {Lukasz M.} and Teo, {Soo Hwang} and Tworoger, {Shelley S.} and Tyrer, {Jonathan P.} and Webb, {Penelope M.} and Nicolas Wentzensen and Emily White and Willett, {Walter C.} and Alicja Wolk and Woo, {Yin Ling} and Wu, {Anna H.} and Li Yan and Drakoulis Yannoukakos and Georgia Chenevix-Trench and Sellers, {Thomas A.} and Pharoah, {Paul D.P.} and Wei Zheng and Jirong Long",

note = "Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",

year = "2019",

month = feb,

day = "1",

doi = "10.1158/0008-5472.CAN-18-2726",

language = "English (US)",

volume = "79",

pages = "505--517",

journal = "Cancer research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "3",

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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 - De Fazio, Anna

AU - Dennis, Joe

AU - Doherty, Jennifer A.

AU - Eccles, Diana M.

AU - Edwards, Digna Velez

AU - Fasching, Peter A.

AU - Fortner, Reneé 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 - Charlotte Onland-Moret, N.

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

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 ¼ 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, ARH-GAP27, 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.

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 ¼ 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, ARH-GAP27, 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.

UR - http://www.scopus.com/inward/record.url?scp=85060947651&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060947651&partnerID=8YFLogxK

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

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

M3 - Article

C2 - 30559148

AN - SCOPUS:85060947651

SN - 0008-5472

VL - 79

SP - 505

EP - 517

JO - Cancer research

JF - Cancer research

IS - 3

ER -

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

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