Citations 2
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.
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.