Citations 4
Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
DeVries, Amber A , Peng, Pei-Chen , Reyes, Alberto Luiz P., Plummer, Jasmine , Davis, Brian , Chen, Stephanie S., Dezem, Felipe Segato , Antonenkova, Natalia, Beckmann, Matthias W. , Beeghly‐Fadiel, Alicia, Bogdanova, Natalia , Bogdanova-Markov, Nadja, Brenton, James D. , Chang‐Claude, Jenny , Dörk, Thilo , Eccles, Diana M, Fasching, Peter A. , Goode, Ellen L. , Goodman, Marc T. , Group, OPAL Study, Grant, Peter , Nagle, C.A., Chevenix-Trench, G, Bowtell, D, Blomfield, Penny, Davis, Alison , Leung, Yee , Livingstone, Karen, O’Neill, Helen C. , Black, Amanda , Hadley, Alison , Shannon, Colleen, Neesham, Deborah, Otton, Geoffrey, Au‐Yeung, George , Goss, Geraldine , Wain, Gerard, Gard, Grace , Robertson, G S M, Lombard, Janine , Tan, Joanne , McNeilage, Jane, Power, J. , Miller, Jessica A., Lamont, John, Wong, Kit Man , Reid, Kate , Milishkin, L, Buck, Martin , Bunting, Michael W, McNally, Orla , Awad, Reda, Mohan, Rahul , Farrell, Rhonda , McIntosh, Rachel, Rome, Robert, Houghton, R., Hogg, Russell , Land, R., Baron‐Hay, Sally , Paramasivum, S, Pather, Selvan , Hyde, Samuel M. , Salfinger, Stuart , Valmadre, Susan, Jobling, Thomas W., Manolitsas, Tom, Bonaventura, T, Group, AOCS, Bowtell, D, Green, A, Webb, P, Gertig, DM, Moore, S., Hung, Jillian A., Harrap, Karen L. , Sadkowsky, T., Malt, M. , Robertson, R. Paul , Bergh, T. Vanden, Jones, Michelle R. , Nattress, K., Chiew, Yoke-Eng, Stenlake, Annie, Ashover, P., Corrish, T., Jackman, Louisa, Ferguson, Kaltin , Martin, Kara, Martyn, Amanda C. , White, Jonathan, Jayde, V., Bowes, Laura, Mamers, Pamela, Galletta, Laura, Giles, Daniel A., Hendley, Joy , Shirley, H., Ball, C., Young, Christian D. , Viduka, S., Bilic, Sanela , Glavinas, Lydia, Brooks, Jacqueline D., Stuart‐Harris, R., Kirsten, Fred, Rutovitz, J , Clingan, P., Proietto, Anthony , Braye, Stephen, Shannon, J., Bonaventura, T, Begbie, Stephen , Hildebrandt, Michelle A.T., Huff, Chad D. , Huntsman, David G., Kar, Siddhartha , Labrie, Marilyne , Lambrechts, Diether , Le, Nhu D. , May, Taymaa, Menon, Usha , Moysich, Kirsten B. , Odunsi, Kunle , Olsson, Håkan , Pearce, Celeste Leigh , Ramus, Susan J. , Ríboli, Elio , Riggan, Marjorie J. , Romieu, Isabelle , Schildkraut, Joellen M. , Sieh, Weiva , Song, Honglin , Sutphen, Rebecca , Terry, Kathryn L. , Thompson, Pamela J., Titus, Linda , Tworoger, Shelley S. , Nieuwenhuysen, Els Van , Edwards, Digna Velez, Wentzensen, Nicolas , Whittemore, Alice S. , Wu, Anna H. , Freedman, Matthew L., Lawrenson, Kate , Easton, Douglas F. , Gayther, Simon A. , Eccles, Diana , Bowtell, David D.L. , Lambrechts, Diether , Dennis, Joe , Plummer, Jasmine T , Anton-Culver, Hoda , Campbell, Ian G , Chenevix-Trench, Georgia , Eliassen, A Heather , Jensen, Allan , Kar, Siddhartha , Menon, Usha , Riboli, Elio , Sieh, Weiva , Webb, Penelope M , Wentzensen, Nicolas , Wolk, Alicja , Ziogas, Argyrios , Lawrenson, Kate , Jones, Michelle R , Dörk, Thilo , Lambrechts, Diether , Ramus, Susan J , Tworoger, Shelley S , Eccles, Diana , Brenton, James D , Moysich, Kirsten , Lambrechts, Diether , Bogdanova, Natalia V , Bowtell, David D , Goodman, Marc T , Tyrer, Jonathan P. , Coetzee, Simon G. , Aben, Katja K.H. , Anton‐Culver, Hoda , Beeghly‐Fadiel, Alicia , Berchuck, Andrew , Bützow, Ralf C. , Campbell, Ian , Chenevix‐Trench, Georgia , Cook, Linda S. , DeFazio, Anna , Doherty, Jennifer A. , Eliassen, A. Heather , Fortner, Renée T. , Giles, Graham G. , Gronwald, Jacek , Group, OPAL Study, Friedländer, Michael , Obermair, Andreas , Nagle, C, Beesley, Vanessa L. , Bowtell, D, Brand, Alison H. , Nicklin, James , Quinn, Michael A. , Williams, M, Hadley, A, Glasgow, A, Garrett, A, Rao, A, Steer, Christopher , Allen, Deborah Emma , Robertson, G, Power, J, Coward, Jermaine , Carter, Jonathan , Lamont, J, Wong, K M, Perrin, Lewis C , Nascimento, M, Buck, M, Harrison, Michelle , Chetty, Naven , Hacker, Neville F. , Harnett, Paul R. , Beale, Philip James , Awad, R, McIntosh, R, Sayer, R, Hogg, R, Hyde, S, Bonaventura, T, Arora, Vivek , Group, AOCS, Bowtell, D, Webb, P, Gertig, Dorota M., Traficante, Nadia , Fereday, Sián , Pandeya, Nirmala , Robertson, R, McKenzie, P, Maidens, J, Sullivan, Helen T. , Alexander, Brian M. , Brown, S, Green, L, Jackman, L, Martyn, A, Ranieri, B, White, J, Giles, D, Alsop, Kathryn , Schmidt, T, Young, C, Tran, H, Rutovitz, J, Glasgow, A, Shannon, J, Bonaventura, T, Stewart, James , Håkansson, Niclas , Hildebrandt, Michelle A.T. , Jensen, Allan , Karlan, Beth Y. , Хуснутдинова, Э. К. , Kiemeney, Lambertus A. , Kjær, Susanne K. , Kupryjańczyk, Jolanta , Lubiński, Jan , Milne, Roger L. , Modugno, Francesmary , Monteiro, Álvaro N.A. , Pejovic, Tanja B. , Sandler, Dale P. , Setiawan, Veronica Wendy , Edwards, Digna R. Velez , Webb, Penelope M. , Wolk, Alicja , Ziogas, Argyrios , Pharoah, Paul D.P.
JNCI: Journal of the National Cancer Institute | October 10, 2022 | Volume: 114 | Issue: 11 | Pages: 1533-1544
AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers
Glubb, Dylan M. , Thompson, Deborah J. , Aben, Katja K.H. , Alsulimani, Ahmad , Amant, Frédéric , Annibali, Daniela , Barricarte, Aurelio , Beckmann, Matthias W. , Bermisheva, Marina , Bernardini, Marcus Q. , Bischof, Katharina , Bodelón, Clara , Brand, Alison H. , Brinton, Louise A. , Bruinsma, Fiona , Burghaus, Stefanie , Cai, Hui , Carney, Michael E. , Chen, Chu , Chen, Xiao Qing, Chen, Zhihua , Cunningham, Julie M. , Vivo, Immaculata De , Dörk, Thilo , Edwards, Todd, Ekici, Arif B. , Ewing, Ailith , Fasching, Peter A. , Ferguson, Sarah, Flanagan, James M. , Fostira, Florentia, Gao, Bo , Gaudet, Mia M. , Gawełko, Jan , Goodman, Marc T. , Harter, Philipp , Hein, Alexander , Hildebrandt, Michelle A.T., Hillemanns, Peter , Høgdall, Claus , Holliday, Elizabeth , Huntsman, David G. , Huzarski, Tomasz , Jones, Michael E. , Kelley, Joseph L., Killeen, Jeffrey , Klapdor, Rüdiger , Köbel, Martin , Konopka, Bożena , Konstantopoulou, Irene , Kopperud, Reidun Kristin, Koti, Madhuri , Lambrechts, Diether , Lele, Shashikant , Lester, Jenny, Li, Andrew J., Liang, Dong , Liebrich, Clemens, Lipworth, Loren , Lissowska, Jolanta , Lu, Karen H., May, Taymaa, McGuire, Valerie , McNeish, Iain A. , Menon, Usha , Moysich, Kirsten B. , Odunsi, Kunle , Olsson, Håkan , Oršulić, Sandra , Osório, Ana , Park‐Simon, Tjoung‐Won , Pearce, Celeste Leigh, Podgórska, Agnieszka , Ramus, Susan J. , Riggan, Marjorie J. , Rothstein, Joseph H. , Runnebaum, Ingo B. , Scott, Rodney J. , Sellers, Thomas A. , Sieh, Weiva , Śpiewankiewicz, Beata, Sutphen, Rebecca , Teo, Soo‐Hwang , Thompson, Pamela J., Titus, Linda , Tone, Alicia , Edwards, Digna Velez, Vergote, Ignace , Wang, Zhaoming , Wang‐Gohrke, Shan , Group, for the OPAL Study, Group, for the AOCS, Whittemore, Alice S. , Wu, Xifeng , Wu, Anna H. , O’Mara, Tracy A. , Lu, Karen H. , Lambrechts, Diether , Barricarte, Aurelio , Bischof, Katharina , Bodelon, Clara , Brenton, James D , Brinton, Louise A , Buchanan, Daniel D , Cunningham, Julie M , De Vivo, Immaculata , Fazio, Anna de , Doherty, Jennifer A , Dörk, Thilo , Dunning, Alison M , Edwards, Todd , Ewing, Ailith , Fasching, Peter A , Flanagan, James M , Friedenreich, Christine M , Gaudet, Mia M , Gawełko, Jan , Gentry‐Maharaj, Aleksandra , Giles, Graham G , Glasspool, Rosalind , Harris, Holly R , Hein, Alexander , Heitz, Florian , Hillemanns, Peter , Jakubowska, Anna , Jones, Michael E , Karlan, Beth Y , Karnezis, Anthony , Kjaer, Susanne K , Klapdor, Rüdiger , Köbel, Martin , Konstantopoulou, Irene , Kupryjanczyk, Jolanta , Lambrechts, Diether , Lissowska, Jolanta , Lu, Lingeng , McAlpine, Jessica N , McNeish, Iain A , Menon, Usha , Nevanlinna, H , Orsulic, Sandra , Palli, Domenico , Park-Simon, Tjoung-Won , Permuth, Jennifer B , Ramus, Susan J , Runnebaum, Ingo B , Sieh, Weiva , Swerdlow, Anthony J , Szafron, Lukasz M , Teo, Soo H , Thompson, Pamela J , Thomsen, Liv Cecilie Vestrheim , Titus, Linda , Tumino, Rosario , Vanderstichele, Adriaan , Vergote, Ignace , Vierkant, Robert A , Webb, Penelope M , Winham, Stacey J , Spurdle, Amanda B , Lambrechts, Diether , Moysich, Kirsten , Wang, Zhaoming , O'Mara, Tracy A , Ekici, Arif B , Amant, Frederic , Høgdall, Claus K , Huzarski, Tomasz , Brand, Alison H , Goodman, Marc T , Attia, John , Berchuck, Andrew , Bjørge, Line , Brenton, James D. , Buchanan, Daniel D. , Bützow, Ralf C. , Chanock, Stephen Jacob , Chen, Xiao Qing, Cook, Linda S. , DeFazio, Anna , Doherty, Jennifer A. , Bois, Andreas du , Dunning, Alison M. , Dürst, Matthias , Fountzilas, George , Giles, Graham G. , Glasspool, Rosalind , Gronwald, Jacek , Harris, Holly R. , Heitz, Florian , Hildebrandt, Michelle A.T. , Høgdall, Estrid , Jakubowska, Anna , Jensen, Allan , Karlan, Beth Y. , Karnezis, Anthony N. , Хуснутдинова, Э. К. , Kjær, Susanne K. , Kraft, Peter , Kupryjańczyk, Jolanta , Larson, Melissa C. , Marchand, Loı̈c Le , Macciotta, Alessandra , Mattiello, Amalia , McAlpine, Jessica N. , Modugno, Francesmary , Nevanlinna, Heli , Palli, Domenico , Pejovic, Tanja B. , Permuth, Jennifer B. , Rebbeck, Timothy R. , Risch, Harvey A. , Senz, Janine , Setiawan, Veronica Wendy , Siddiqui, Nadeem , Swerdlow, Anthony J. , Szafron, Lukasz M. , Thomsen, Liv Cecilie Vestrheim , Tumino, Rosario , Turman, Constance , Vanderstichele, Adriaan , Edwards, Digna R. Velez , Vierkant, Robert A. , Webb, Penelope M. , Group, for the OPAL Study, Group, for the AOCS, White, Emily , Winham, Stacey J. , Yannoukakos, Drakoulis , Spurdle, Amanda B.
Cancer Epidemiology, Biomarkers & Prevention | November 3, 2020 | Volume: 30 | Issue: 1 | Pages: 217-228
Abstract Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk
Yang, Yaohua , Wu, Lang , Shu, Xiao-Ou , Lu, Yingchang , Beeghly‐Fadiel, Alicia, Li, Bingshan , Ye, Fei , Banerjee, Susana , Benı́tez, Javier , Chang‐Claude, Jenny , Chen, Kexin , DeFazio, Anna , Dörk, Thilo , Eccles, Diana M., Edwards, Digna Velez, Fasching, Peter A. , Fortner, Renée T. , Gayther, Simon A. , Goode, Ellen L. , Goodman, Marc T. , Heitz, Florian , Hildebrandt, Michelle A.T., Høgdall, Estrid , Høgdall, Claus , Huntsman, David G. , Kar, Siddhartha , Kelemen, Linda E. , Koushik, Anita , Lambrechts, Diether , Le, Nhu D. , Levine, Douglas A. , Massuger, Leon F.A.G. , Matsuo, Keitaro , May, Taymaa, McNeish, Iain A. , Menon, Usha , Monteiro, Álvaro N.A. , Moorman, Patricia G. , Moysich, Kirsten B. , Ness, Roberta B., Olsson, Håkan , Onland‐Moret, N. Charlotte , Park, Sue K. , Paul, James , Pearce, Celeste Leigh, Phelan, Catherine M., Pike, Malcolm C. , Ramus, Susan J. , Ríboli, Elio , Rodríguez‐Antona, Cristina , Romieu, Isabelle, Sandler, Dale P. , Schildkraut, Joellen M. , Shan, Kang, Sieh, Weiva , Stampfer, Meir J. , Sutphen, Rebecca , Swerdlow, Anthony J. , Szafron, Lukasz M. , Teo, Soo‐Hwang , Tworoger, Shelley S. , Webb, Penelope M. , Wentzensen, Nicolas , Woo, Yin Ling , Wu, Anna H. , Chenevix‐Trench, Georgia , Sellers, Thomas A. , Long, Jirong , Eccles, Diana , Lambrechts, Diether , Chen, Kexin , Shu, Xiao-Ou , Brenton, James D , Chang-Claude, Jenny , Fazio, Anna de , Dennis, Joe , Fasching, Peter A , Fortner, Renée T , Giles, Graham G , Harris, Holly R , Kiemeney, Lambertus A , Kjaer, Susanne K , Koushik, Anita , McNeish, Iain A , Menon, Usha , Monteiro, Alvaro N , Nevanlinna, H , Park, Sue K , Paul, James , Ramus, Susan J , Rodríguez-Antona, Cristina , Sandler, Dale P , Szafron, Lukasz M , Teo, Soo H , Tworoger, Shelley S , Webb, Penelope M , Wolk, Alicja , Dörk, Thilo , Lambrechts, Diether , Eccles, Diana , Swerdlow, Anthony J , Moysich, Kirsten , Matsuo, Keitaro , Heitz, Florian , Lambrechts, Diether , Sieh, Weiva , Benitez, Javier , Chenevix-Trench, Georgia , Høgdall, Estrid , Høgdall, Claus K , Kar, Siddhartha , Riboli, Elio , Goodman, Marc T , Cai, Qiuyin , Beeghly‐Fadiel, Alicia , Berchuck, Andrew , Anton‐Culver, Hoda , Bjørge, Line , Brenton, James D. , Bützow, Ralf C. , Campbell, Ian , Cook, Linda S. , Cramer, Daniel W. , Doherty, Jennifer A. , Edwards, Digna R. Velez , Giles, Graham G. , Glasspool, Rosalind , Gronwald, Jacek , Harris, Holly R. , Hildebrandt, Michelle A.T. , Karlan, Beth Y. , Kiemeney, Lambertus A. , Kjær, Susanne K. , Modugno, Francesmary , Nevanlinna, Heli , Pejovic, Tanja B. , Setiawan, Veronica Wendy , Shan, Kang, Siddiqui, Nadeem , Tyrer, Jonathan P. , White, Emily , Willett, Walter C. , Wolk, Alicja , Li, Yan , Yannoukakos, Drakoulis , Pharoah, Paul D.P. , Zheng, Wei , Yang, Yaohua
Cancer Research | December 17, 2018 | Volume: 79 | Issue: 3 | Pages: 505-517
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. 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.
A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk
Lu, Yingchang , Beeghly‐Fadiel, Alicia, Wu, Lang , Li, Bingshan , Schildkraut, Joellen M. , Im, Hae Kyung , Chen, Y. Ann , Permuth, Jennifer B. , Reid, Brett M. , Teer, Jamie K. , Moysich, Kirsten B., Andrulis, Irene L. , Barkardóttir, Rósa B. , Benı́tez, Javier , Caldés, Trinidad , Chang‐Claude, Jenny , Claes, Kathleen , Daly, Mary B., DeFazio, Anna , Dörk, Thilo , Easton, Douglas F. , Eccles, Diana M., Fasching, Peter A. , Fortner, Renée T. , Fountzilas, George , Friedman, Eitan , Ganz, Patricia A. , Goldgar, David E., Goodman, Marc T. , Greene, Mark H. , Hamann, Ute, Heitz, Florian , Hildebrandt, Michelle A.T., Høgdall, Claus , Hulick, Peter J. , Huntsman, David G. , Imyanitov, Evgeny N., Jakubowska, Anna , James, Paul A. , Kelemen, Linda E., Kwong, Ava , Le, Nhu D., Lesueur, Fabienne , May, Taymaa, McGuffog, Lesley, McNeish, Iain A. , Merritt, Melissa A. , Montagna, Marco , Ņikitina-Zaķe, Liene , Offit, Kenneth, Oláh, Edith , Olopade, Olufunmilayo I. , Olsson, Håkan , Osório, Ana , Park, Sue K. , Peeters, Petra H.M. , Peterlongo, Paolo , Phelan, Catherine M., Pujana, Miguel Ángel , Ramus, Susan J. , Rennert, Gad , Rodriguez, Gustavo C. , Rodríguez‐Antona, Cristina , Romieu, Isabelle , Rookus, Matti A. , Rossing, Mary Anne, Rzepecka, Iwona K. , Schmutzler, Rita K., Sieh, Weiva , Simard, Jacques , Song, Honglin , Sutphen, Rebecca , Swerdlow, Anthony J. , Teixeira, Manuel R. , Teo, Soo‐Hwang , Thomassen, Mads , Trichopoulou, Antonia , Tworoger, Shelley S. , Rensburg, Elizabeth J. van , Vega, Ana , Edwards, Digna Velez, Webb, Penelope M. , Weitzel, Jeffrey N. , Wentzensen, Nicolas , Wu, Anna H. , Zorn, Kristin K. , Gayther, Simon A. , Antoniou, Antonis C. , Goode, Ellen L. , Chenevix‐Trench, Georgia , Sellers, Thomas A. , Long, Jirong , Durocher, Francine , Eccles, Diana , Permuth, Jennifer B , Teer, Jamie K , Barnes, Daniel R , Caldes, Trinidad , Caligo, Maria A , Chang-Claude, Jenny , Fazio, Anna de , Dennis, Joe , Fasching, Peter A , Fortner, Renée T , Garber, J. E. , Giles, Graham G , Greene, Mark H , Hulick, Peter J , Isaacs, Claudine , James, Paul , Kiemeney, Lambertus A , Kjaer, Susanne K , Leslie, Goska , Lesueur, Fabienne , McNeish, Iain A , Nevanlinna, H , Nussbaum, Robert , Park, Sue K , Parsons, Michael T , Peterlongo, Paolo , Pujana, Miquel Angel , Ramus, Susan J , Rennert, Gad , Rodríguez-Antona, Cristina , Sandler, Dale P , Spurdle, Amanda B , Teixeira, Manuel R , Teo, Soo H , Tworoger, Shelley S , van Rensburg, Elizabeth J , Vanderstichele, Adriaan , Webb, Penelope M , Wolk, Alicja , Dörk, Thilo , Eccles, Diana , Swerdlow, Anthony J , Moysich, Kirsten , Vega, Ana , Weitzel, Jeffrey N , Claes, Kathleen B M , Olopade, Olufunmilayo I , Heitz, Florian , Jakubowska, Anna , Sieh, Weiva , Benitez, Javier , Montagna, Marco , Simard, Jacques , Chenevix-Trench, Georgia , Høgdall, Claus K , Goodman, Marc T , Beeghly‐Fadiel, Alicia , Guo, Xingyi , Moysich, Kirsten B. , Anton‐Culver, Hoda , Arun, Banu , Bandera, Elisa V. , Barnes, Daniel R. , Bjørge, Line , Brenton, James D. , Bützow, Ralf C. , Caligo, Maria A. , Campbell, Ian , Couch, Fergus J. , Cramer, Daniel W. , Dı́ez, Orland , Domchek, Susan M. , Garber, Judy E. , Giles, Graham G. , Godwin, Andrew K. , Gronwald, Jacek , Hildebrandt, Michelle A.T. , Hollestelle, Antoinette , Isaacs, Claudine , Karlan, Beth Y. , Kiemeney, Lambertus A. , Kjær, Susanne K. , Leslie, Goska , Levine, Douglas A. , Mattiello, Amalia , Modugno, Francesmary , Neuhausen, Susan L. , Nevanlinna, Heli , Nielsen, Finn Cilius , Nussbaum, Robert L. , Olson, Sara H. , Parsons, Michael T. , Pejovic, Tanja B. , Risch, Harvey A. , Sandler, Dale P. , Setiawan, Veronica Wendy , Sharma, Priyanka , Singer, Christian F. , Southey, Melissa C. , Spurdle, Amanda B. , Tischkowitz, Marc D. , Toland, Amanda Ewart , Tung, Nadine , Vanderstichele, Adriaan , Edwards, Digna R. Velez , White, Emily , Wolk, Alicja , Yannoukakos, Drakoulis , Berchuck, Andrew , Pharoah, Paul D.P. , Zheng, Wei , Kwong, Ava , Im, H K
Cancer Research | July 27, 2018 | Volume: 78 | Issue: 18 | Pages: 5419-5430
Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.