Advanced

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue and Lee, Janet M, et al. (2015) In Nature Genetics 47(2). p.71-164
Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2),... (More)

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adolescent, Adult, Alleles, BRCA1 Protein, BRCA2 Protein, Female, Genes, Reporter, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heterozygote, Humans, Mutation, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Young Adult, Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
in
Nature Genetics
volume
47
issue
2
pages
8 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:25581431
  • wos:000348694700012
  • scopus:84929171835
ISSN
1546-1718
DOI
10.1038/ng.3185
language
English
LU publication?
yes
id
64aad5fe-991c-4959-a907-af91c0c9011e (old id 5040500)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25581431?dopt=Abstract
date added to LUP
2015-02-02 21:41:01
date last changed
2017-11-17 13:00:02
@article{64aad5fe-991c-4959-a907-af91c0c9011e,
  abstract     = {<p>Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P &lt; 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.</p>},
  author       = {Kuchenbaecker, Karoline B and Ramus, Susan J and Tyrer, Jonathan and Lee, Andrew and Shen, Howard C and Beesley, Jonathan and Lawrenson, Kate and McGuffog, Lesley and Healey, Sue and Lee, Janet M and Spindler, Tassja J and Lin, Yvonne G and Pejovic, Tanja and Bean, Yukie and Li, Qiyuan and Coetzee, Simon and Hazelett, Dennis and Miron, Alexander and Southey, Melissa and Terry, Mary Beth and Goldgar, David E and Buys, Saundra S and Janavicius, Ramunas and Dorfling, Cecilia M and van Rensburg, Elizabeth J and Neuhausen, Susan L and Ding, Yuan Chun and Hansen, Thomas V O and Jønson, Lars and Gerdes, Anne-Marie and Ejlertsen, Bent and Barrowdale, Daniel and Dennis, Joe and Benitez, Javier and Osorio, Ana and Garcia, Maria Jose and Komenaka, Ian and Weitzel, Jeffrey N and Ganschow, Pamela and Peterlongo, Paolo and Bernard, Loris and Viel, Alessandra and Bonanni, Bernardo and Peissel, Bernard and Manoukian, Siranoush and Radice, Paolo and Papi, Laura and Ottini, Laura and Fostira, Florentia and Konstantopoulou, Irene and Garber, Judy and Frost, Debra and Perkins, Jo and Platte, Radka and Ellis, Steve and Godwin, Andrew K and Schmutzler, Rita Katharina and Meindl, Alfons and Engel, Christoph and Sutter, Christian and Sinilnikova, Olga M and Damiola, Francesca and Mazoyer, Sylvie and Stoppa-Lyonnet, Dominique and Claes, Kathleen and De Leeneer, Kim and Kirk, Judy and Rodriguez, Gustavo C and Piedmonte, Marion and O'Malley, David M and de la Hoya, Miguel and Caldes, Trinidad and Aittomäki, Kristiina and Nevanlinna, Heli and Collée, J Margriet and Rookus, Matti A and Oosterwijk, Jan C and Tihomirova, Laima and Tung, Nadine and Hamann, Ute and Isaccs, Claudine and Tischkowitz, Marc and Imyanitov, Evgeny N and Caligo, Maria A and Campbell, Ian G and Hogervorst, Frans B L and Olah, Edith and Diez, Orland and Blanco, Ignacio and Brunet, Joan and Lazaro, Conxi and Pujana, Miquel Angel and Jakubowska, Anna and Gronwald, Jacek and Lubinski, Jan and Sukiennicki, Grzegorz and Barkardottir, Rosa B and Plante, Marie and Simard, Jacques and Soucy, Penny and Montagna, Marco and Tognazzo, Silvia and Teixeira, Manuel R and Pankratz, Vernon S and Wang, Xianshu and Lindor, Noralane and Szabo, Csilla I and Kauff, Noah and Vijai, Joseph and Aghajanian, Carol A and Pfeiler, Georg and Berger, Andreas and Singer, Christian F and Tea, Muy-Kheng and Phelan, Catherine M and Greene, Mark H and Mai, Phuong L and Rennert, Gad and Mulligan, Anna Marie and Tchatchou, Sandrine and Andrulis, Irene L and Glendon, Gord and Toland, Amanda Ewart and Jensen, Uffe Birk and Kruse, Torben A and Thomassen, Mads and Bojesen, Anders and Zidan, Jamal and Friedman, Eitan and Laitman, Yael and Soller, Maria and Liljegren, Annelie and Arver, Brita and Einbeigi, Zakaria and Stenmark-Askmalm, Marie and Olopade, Olufunmilayo I and Nussbaum, Robert L and Rebbeck, Timothy R and Nathanson, Katherine L and Domchek, Susan M and Lu, Karen H and Karlan, Beth Y and Walsh, Christine and Lester, Jenny and Hein, Alexander and Ekici, Arif B and Beckmann, Matthias W and Fasching, Peter A and Lambrechts, Diether and Van Nieuwenhuysen, Els and Vergote, Ignace and Lambrechts, Sandrina and Dicks, Ed and Doherty, Jennifer A and Wicklund, Kristine G and Rossing, Mary Anne and Rudolph, Anja and Chang-Claude, Jenny and Wang-Gohrke, Shan and Eilber, Ursula and Moysich, Kirsten B and Odunsi, Kunle and Sucheston, Lara and Lele, Shashi and Wilkens, Lynne R and Goodman, Marc T and Thompson, Pamela J and Shvetsov, Yurii B and Runnebaum, Ingo B and Dürst, Matthias and Hillemanns, Peter and Dörk, Thilo and Antonenkova, Natalia and Bogdanova, Natalia and Leminen, Arto and Pelttari, Liisa M and Butzow, Ralf and Modugno, Francesmary and Kelley, Joseph L and Edwards, Robert P and Ness, Roberta B and du Bois, Andreas and Heitz, Florian and Schwaab, Ira and Harter, Philipp and Matsuo, Keitaro and Hosono, Satoyo and Orsulic, Sandra and Jensen, Allan and Kjaer, Susanne Kruger and Hogdall, Estrid and Hasmad, Hanis Nazihah and Azmi, Mat Adenan Noor and Teo, Soo-Hwang and Woo, Yin-Ling and Fridley, Brooke L and Goode, Ellen L and Cunningham, Julie M and Vierkant, Robert A and Bruinsma, Fiona and Giles, Graham G and Liang, Dong and Hildebrandt, Michelle A T and Wu, Xifeng and Levine, Douglas A and Bisogna, Maria and Berchuck, Andrew and Iversen, Edwin S and Schildkraut, Joellen M and Concannon, Patrick and Weber, Rachel Palmieri and Cramer, Daniel W and Terry, Kathryn L and Poole, Elizabeth M and Tworoger, Shelley S and Bandera, Elisa V and Orlow, Irene and Olson, Sara H and Krakstad, Camilla and Salvesen, Helga B and Tangen, Ingvild L and Bjorge, Line and van Altena, Anne M and Aben, Katja K H and Kiemeney, Lambertus A and Massuger, Leon F A G and Kellar, Melissa and Brooks-Wilson, Angela and Kelemen, Linda E and Cook, Linda S and Le, Nhu D and Cybulski, Cezary and Yang, Hannah and Lissowska, Jolanta and Brinton, Louise A and Wentzensen, Nicolas and Hogdall, Claus and Lundvall, Lene and Nedergaard, Lotte and Baker, Helen and Song, Honglin and Eccles, Diana and McNeish, Ian and Paul, James and Carty, Karen and Siddiqui, Nadeem and Glasspool, Rosalind and Whittemore, Alice S and Rothstein, Joseph H and McGuire, Valerie and Sieh, Weiva and Ji, Bu-Tian and Zheng, Wei and Shu, Xiao-Ou and Gao, Yu-Tang and Rosen, Barry and Risch, Harvey A and McLaughlin, John R and Narod, Steven A and Monteiro, Alvaro N and Chen, Ann and Lin, Hui-Yi and Permuth-Wey, Jenny and Sellers, Thomas A and Tsai, Ya-Yu and Chen, Zhihua and Ziogas, Argyrios and Anton-Culver, Hoda and Gentry-Maharaj, Aleksandra and Menon, Usha and Harrington, Patricia and Lee, Alice W and Wu, Anna H and Pearce, Celeste L and Coetzee, Gerry and Pike, Malcolm C and Dansonka-Mieszkowska, Agnieszka and Timorek, Agnieszka and Rzepecka, Iwona K and Kupryjanczyk, Jolanta and Freedman, Matt and Noushmehr, Houtan and Easton, Douglas F and Offit, Kenneth and Couch, Fergus J and Gayther, Simon and Pharoah, Paul P and Antoniou, Antonis C and Chenevix-Trench, Georgia and , },
  issn         = {1546-1718},
  keyword      = {Adolescent,Adult,Alleles,BRCA1 Protein,BRCA2 Protein,Female,Genes, Reporter,Genetic Predisposition to Disease,Genome-Wide Association Study,Genotype,Heterozygote,Humans,Mutation,Neoplasms, Glandular and Epithelial,Ovarian Neoplasms,Polymorphism, Single Nucleotide,Quantitative Trait Loci,Risk,Young Adult,Journal Article,Meta-Analysis,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {2},
  pages        = {71--164},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Identification of six new susceptibility loci for invasive epithelial ovarian cancer},
  url          = {http://dx.doi.org/10.1038/ng.3185},
  volume       = {47},
  year         = {2015},
}