Citations 3
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.
Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus
Buckley, Melissa A., Woods, Nicholas T. , Mendoza-Fandiño, Gustavo, Lawrenson, Kate , Hazelett, Dennis J. , Najafabadi, Hamed S. , Gjyshi, Anxhela, Carvalho, Renato S. , Lyra, Paulo C. , Shen, Howard C., Yang, Ally , Earp, Madalene A. , Yoder, Sean J., Chenevix‐Trench, Georgia , Ramus, Susan J. , Phelan, Catherine M., Coetzee, Gerhard A., Hughes, Timothy R. , Sellers, Thomas A. , Goode, Ellen L. , Gayther, Simon A. , Monteiro, Álvaro N.A. , Lu, Karen H. , Goodman, Marc T. , Lissowska, Jolanta , Jakubowska, Anna , Dörk, Thilo , Matsuo, Keitaro , Menon, Usha , Terry, Kathryn L. , Tworoger, Shelley S. , Ekici, Arif B. , Chen, Y. Ann , Eccles, Diana , Teo, Soo‐Hwang , Hein, Alexander , Hillemanns, Peter , Lambrechts, Diether , Jensen, Allan , Brooks‐Wilson, Angela , Sieh, Weiva , Dansonka‐Mieszkowska, Agnieszka , Liang, Dong , Woo, Yin Ling , McNeish, Iain A. , Lambrechts, Diether , Lawrenson, Kate , Hazelett, Dennis J , Najafabadi, Hamed S , Coetzee, Simon G , Ramus, Susan J , Noushmehr, Houtan , Dörk, Thilo , Lambrechts, Diether , McNeish, Iain A , Teo, Soo H , Tworoger, Shelley S , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Eccles, Diana , Menon, Usha , Monteiro, Alvaro N , Lissowska, Jolanta , Brooks-Wilson, Angela R , Matsuo, Keitaro , Jakubowska, Anna , Lambrechts, Diether , Sieh, Weiva , Ekici, Arif B , Chenevix-Trench, Georgia , Goodman, Marc T , Tyrer, Jonathan P. , Coetzee, Simon G. , Yoder, Sean , Risch, Harvey A. , Noushmehr, Houtan , Pharoah, Paul D.P. , Morais Lyra, Paulo Cilas
Cancer Research | November 28, 2018 | Volume: 79 | Issue: 3 | Pages: 467-481
Abstract Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439
Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci
Coetzee, Simon G. , Shen, Howard C., Hazelett, Dennis J. , Lawrenson, Kate , Kuchenbaecker, Karoline , Rhie, Suhn K. , Levanon, Keren , Karst, Alison M., Drapkin, Ronny , Ramus, Susan J. , Offit, Kenneth, Chenevix‐Trench, Georgia , Monteiro, Álvaro N.A. , Antoniou, Antonis C. , Freedman, Matthew L., Coetzee, Gerhard A. , Gayther, Simon A. , Antonenkova, Natalia, Bean, Yukie T., Beckmann, Matthias W. , Bisogna, Maria, Bogdanova, Natalia , Brinton, Louise A. , Bruinsma, Fiona , Chang‐Claude, Jenny, Chen, Ann , Chen, Zhihua , Cunningham, Julie M. , Dansonka‐Mieszkowska, Agnieszka , Dicks, Ed , Dörk, Thilo , Eccles, Diana , Easton, Douglas F. , Edwards, Robert P., Eilber, Ursula, Ekici, Arif B. , Fasching, Peter A. , Gao, Yu‐Tang , Giles, Graham G. , Glasspool, Rosalind , Goode, Ellen L. , Grownwald, Jacek, Harrington, Patricia, Harter, Philipp , Hasmad, Hanis Nazihah, Hein, Alexander , Heitz, Florian , Hildebrandt, Michelle A.T., Hillemanns, Peter , Høgdall, Claus , Hosono, Satoyo , Iversen, Edwin S., Jakubowska, Anna , James, Paul A. , Jensen, Allan , Ji, Bu‐Tian , Kjær, Susanne K. , Kelemen, Linda E. , Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A. , Krakstad, Camilla , Kupryjańczyk, Jolanta , Lambrechts, Diether , Lambrechts, Sandrina, Le, Nhu D. , Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A. , Lissowska, Jolanta , Lu, Karen, Lubiński, Jan , Lundvall, Lene, Massuger, Leon F.A.G. , Matsuo, Keitaro , McGuire, Valerie , McLaughlin, John R., McNeish, Ian, Menon, Usha , Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte , Ness, Roberta B., Azmi, Mat Adenan Noor, Odunsi, Kunle , Oršulić, Sandra , Pearce, Celeste Leigh, Pelttari, Liisa M. , Permuth‐Wey, Jennifer, Phelan, Catherine M., Pike, Malcolm C., Rossing, Mary Anne, Rothstein, Joseph H. , Runnebaum, Ingo B., Rzepecka, Iwona K. , Salvesen, Helga B., Schildkraut, Joellen M. , Schwaab, Ira, Sellers, Thomas A. , Shu, Xiao‐Ou, Shvetsov, Yurii B. , Sieh, Weiva , Song, Honglin , Southey, Melissa C. , Sucheston, Lara, Tangen, Ingvild L. , Teo, Soo‐Hwang , Thompson, Pamela J., Timorek, Agnieszka, Tworoger, Shelley S. , Altena, Anne M. van , Nieuwenhuysen, Els Van , Vergote, Ignace , Vierkant, Robert A. , Wang‐Gohrke, Shan , Walsh, Christine , Wentzensen, Nicolas, Whittemore, Alice S. , Wicklund, Kristine G. , Woo, Yin Ling , Wu, Xifeng , Wu, Anna H. , Lu, Karen H. , McNeish, Iain A. , Lambrechts, Diether , Tyrer, Jonathan P. , Couch, Fergus J. , Pharoah, Paul D.P. , Noushmehr, Houtan , Anton‐Culver, Hoda , Baker, Helen H. , Bandera, Elisa V. , Berchuck, Andrew , Bjørge, Line , Brooks‐Wilson, Angela , Bützow, Ralf C. , Campbell, Ian , Carty, Karen , Cook, Linda S. , Cramer, Daniel W. , Cybulski, Cezary , Dennis, Joe , Doherty, Jennifer A. , Bois, Andreas du , Dürst, Matthias , Fridley, Brooke L. , Gentry‐Maharaj, Aleksandra , Goodman, Marc T. , Hildebrandt, Michelle A.T. , Høgdall, Estrid , Karlan, Beth Y. , Lester, Jenny, Liang, Dong , Lu, Karen, McLaughlin, John R., McNeish, Ian, Modugno, Francesmary , Olson, Sara H. , Orlow, Irene , Weber, Rachel Palmieri , Pejovic, Tanja B. , Poole, Elizabeth M. , Risch, Harvey A. , Rosen, Barry P. , Rudolph, Anja , Siddiqui, Nadeem , Terry, Kathryn L. , Wentzensen, Nicolas , Wilkens, Lynne R. , Yang, Hannah , Zheng, Wei , Ziogas, Argyrios , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , James, Paul , Kiemeney, Lambertus A , Kjaer, Susanne K , McNeish, Iain A , Ramus, Susan J , Teo, Soo H , Tworoger, Shelley S , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Lawrenson, Kate , Hazelett, Dennis J , Coetzee, Simon G , Monteiro, Alvaro N , Lissowska, Jolanta , Southey, Melissa C , Glasspool, Rosalind , Matsuo, Keitaro , Heitz, Florian , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Ekici, Arif B , Bogdanova, Natalia V , Chenevix-Trench, Georgia , Drapkin, Ronny , Høgdall, Claus K , Lubinski, Jan
Human Molecular Genetics | March 24, 2015 | Volume: 24 | Issue: 13 | Pages: 3595-3607