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), 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 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
| Original language | English |
|---|---|
| Pages (from-to) | 164-171 |
| Number of pages | 8 |
| Journal | Nature Genetics |
| Volume | 47 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jan 1 2015 |
ASJC Scopus subject areas
- Genetics
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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; Lee, Janet M.; Spindler, Tassja J.; Lin, Yvonne G.; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; Van Rensburg, Elizabeth J.; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Gerdes, Anne Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N.; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Frost, Debra; Perkins, Jo; Platte, Radka; Ellis, Steve; Godwin, Andrew K.; Schmutzler, Rita Katharina; Meindl, Alfons; Engel, Christoph; Sutter, Christian; Sinilnikova, Olga M.; Damiola, Francesca; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Claes, Kathleen; De Leeneer, Kim; Kirk, Judy; Rodriguez, Gustavo C.; Piedmonte, Marion; O'Malley, David M.; De La Hoya, Miguel; Caldes, Trinidad; Aittomäki, Kristiina; Nevanlinna, Heli; Margriet, J. Collée; Rookus, Matti A.; Oosterwijk, Jan C.; Tihomirova, Laima; Tung, Nadine; Hamann, Ute; Isaccs, Claudine; Tischkowitz, Marc; Imyanitov, Evgeny N.; Caligo, Maria A.; Campbell, Ian G.; Hogervorst, Frans B L; Olah, Edith; Diez, Orland; Blanco, Ignacio; Brunet, Joan; Lazaro, Conxi; Pujana, Miquel Angel; Jakubowska, Anna; Gronwald, Jacek; Lubinski, Jan; Sukiennicki, Grzegorz; Barkardottir, Rosa B.; Plante, Marie; Simard, Jacques; Soucy, Penny; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R.; Pankratz, Vernon S.; Wang, Xianshu; Lindor, Noralane; Szabo, Csilla I.; Kauff, Noah; Vijai, Joseph; Aghajanian, Carol A.; Pfeiler, Georg; Berger, Andreas; Singer, Christian F.; Tea, Muy Kheng; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Tchatchou, Sandrine; Andrulis, Irene L.; Glendon, Gord; Toland, Amanda Ewart; Jensen, Uffe Birk; Kruse, Torben A.; Thomassen, Mads; Bojesen, Anders; Zidan, Jamal; Friedman, Eitan; Laitman, Yael; Soller, Maria; Liljegren, Annelie; Arver, Brita; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Rebbeck, Timothy R.; Nathanson, Katherine L.; Domchek, Susan M.; Lu, Karen H.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Fasching, Peter A.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambrechts, Sandrina; Dicks, Ed; Doherty, Jennifer A.; Wicklund, Kristine G.; Rossing, Mary Anne; Rudolph, Anja; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Moysich, Kirsten B.; Odunsi, Kunle; Sucheston, Lara; Lele, Shashi; Wilkens, Lynne R.; Goodman, Marc T.; Thompson, Pamela J.; Shvetsov, Yurii B.; Runnebaum, Ingo B.; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Pelttari, Liisa M.; Butzow, Ralf; Modugno, Francesmary; Kelley, Joseph L.; Edwards, Robert P.; Ness, Roberta B.; Du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Matsuo, Keitaro; Hosono, Satoyo; Orsulic, Sandra; Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid; Hasmad, Hanis Nazihah; Noor Azmi, Mat Adenan; Teo, Soo Hwang; Woo, Yin Ling; Fridley, Brooke L.; Goode, Ellen L.; Cunningham, Julie M.; Vierkant, Robert A.; Bruinsma, Fiona; Giles, Graham G.; Liang, Dong; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A.; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S.; Schildkraut, Joellen M.; Concannon, Patrick; Weber, Rachel Palmieri; Cramer, Daniel W.; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.; Bandera, Elisa V.; Orlow, Irene; Olson, Sara H.; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.; Bjorge, Line; Van Altena, Anne M.; Aben, Katja K H; Kiemeney, Lambertus A.; Massuger, Leon F A G; Kellar, Melissa; Brooks-Wilson, Angela; Kelemen, Linda E.; Cook, Linda S.; Le, Nhu D.; Cybulski, Cezary; Yang, Hannah; Lissowska, Jolanta; Brinton, Louise A.; Wentzensen, Nicolas; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Baker, Helen; Song, Honglin; Eccles, Diana; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S.; Rothstein, Joseph H.; McGuire, Valerie; Sieh, Weiva; Ji, Bu Tian; Zheng, Wei; Shu, Xiao Ou; Gao, Yu Tang; Rosen, Barry; Risch, Harvey A.; McLaughlin, John R.; Narod, Steven A.; Monteiro, Alvaro N.; Chen, Ann; Lin, Hui Yi; Permuth-Wey, Jenny; Sellers, Thomas A.; Tsai, Ya Yu; Chen, Zhihua; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Harrington, Patricia; Lee, Alice W.; Wu, Anna H.; Pearce, Celeste L.; Coetzee, Gerry; Pike, Malcolm C.; Dansonka-Mieszkowska, Agnieszka; Timorek, Agnieszka; Rzepecka, Iwona K.; Kupryjanczyk, Jolanta; Freedman, Matt; Noushmehr, Houtan; Easton, Douglas F.; Offit, Kenneth; Couch, Fergus J.; Gayther, Simon; Pharoah, Paul P.; Antoniou, Antonis C.; Chenevix-Trench, Georgia.
In: Nature Genetics, Vol. 47, No. 2, 01.01.2015, p. 164-171.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Identification of six new susceptibility loci for invasive epithelial ovarian cancer
AU - Kuchenbaecker, Karoline B.
AU - Ramus, Susan J.
AU - Tyrer, Jonathan
AU - Lee, Andrew
AU - Shen, Howard C.
AU - Beesley, Jonathan
AU - Lawrenson, Kate
AU - McGuffog, Lesley
AU - Healey, Sue
AU - Lee, Janet M.
AU - Spindler, Tassja J.
AU - Lin, Yvonne G.
AU - Pejovic, Tanja
AU - Bean, Yukie
AU - Li, Qiyuan
AU - Coetzee, Simon
AU - Hazelett, Dennis
AU - Miron, Alexander
AU - Southey, Melissa
AU - Terry, Mary Beth
AU - Goldgar, David E.
AU - Buys, Saundra S.
AU - Janavicius, Ramunas
AU - Dorfling, Cecilia M.
AU - Van Rensburg, Elizabeth J.
AU - Neuhausen, Susan L.
AU - Ding, Yuan Chun
AU - Hansen, Thomas V O
AU - Jønson, Lars
AU - Gerdes, Anne Marie
AU - Ejlertsen, Bent
AU - Barrowdale, Daniel
AU - Dennis, Joe
AU - Benitez, Javier
AU - Osorio, Ana
AU - Garcia, Maria Jose
AU - Komenaka, Ian
AU - Weitzel, Jeffrey N.
AU - Ganschow, Pamela
AU - Peterlongo, Paolo
AU - Bernard, Loris
AU - Viel, Alessandra
AU - Bonanni, Bernardo
AU - Peissel, Bernard
AU - Manoukian, Siranoush
AU - Radice, Paolo
AU - Papi, Laura
AU - Ottini, Laura
AU - Fostira, Florentia
AU - Konstantopoulou, Irene
AU - Garber, Judy
AU - Frost, Debra
AU - Perkins, Jo
AU - Platte, Radka
AU - Ellis, Steve
AU - Godwin, Andrew K.
AU - Schmutzler, Rita Katharina
AU - Meindl, Alfons
AU - Engel, Christoph
AU - Sutter, Christian
AU - Sinilnikova, Olga M.
AU - Damiola, Francesca
AU - Mazoyer, Sylvie
AU - Stoppa-Lyonnet, Dominique
AU - Claes, Kathleen
AU - De Leeneer, Kim
AU - Kirk, Judy
AU - Rodriguez, Gustavo C.
AU - Piedmonte, Marion
AU - O'Malley, David M.
AU - De La Hoya, Miguel
AU - Caldes, Trinidad
AU - Aittomäki, Kristiina
AU - Nevanlinna, Heli
AU - Margriet, J. Collée
AU - Rookus, Matti A.
AU - Oosterwijk, Jan C.
AU - Tihomirova, Laima
AU - Tung, Nadine
AU - Hamann, Ute
AU - Isaccs, Claudine
AU - Tischkowitz, Marc
AU - Imyanitov, Evgeny N.
AU - Caligo, Maria A.
AU - Campbell, Ian G.
AU - Hogervorst, Frans B L
AU - Olah, Edith
AU - Diez, Orland
AU - Blanco, Ignacio
AU - Brunet, Joan
AU - Lazaro, Conxi
AU - Pujana, Miquel Angel
AU - Jakubowska, Anna
AU - Gronwald, Jacek
AU - Lubinski, Jan
AU - Sukiennicki, Grzegorz
AU - Barkardottir, Rosa B.
AU - Plante, Marie
AU - Simard, Jacques
AU - Soucy, Penny
AU - Montagna, Marco
AU - Tognazzo, Silvia
AU - Teixeira, Manuel R.
AU - Pankratz, Vernon S.
AU - Wang, Xianshu
AU - Lindor, Noralane
AU - Szabo, Csilla I.
AU - Kauff, Noah
AU - Vijai, Joseph
AU - Aghajanian, Carol A.
AU - Pfeiler, Georg
AU - Berger, Andreas
AU - Singer, Christian F.
AU - Tea, Muy Kheng
AU - Phelan, Catherine M.
AU - Greene, Mark H.
AU - Mai, Phuong L.
AU - Rennert, Gad
AU - Mulligan, Anna Marie
AU - Tchatchou, Sandrine
AU - Andrulis, Irene L.
AU - Glendon, Gord
AU - Toland, Amanda Ewart
AU - Jensen, Uffe Birk
AU - Kruse, Torben A.
AU - Thomassen, Mads
AU - Bojesen, Anders
AU - Zidan, Jamal
AU - Friedman, Eitan
AU - Laitman, Yael
AU - Soller, Maria
AU - Liljegren, Annelie
AU - Arver, Brita
AU - Einbeigi, Zakaria
AU - Stenmark-Askmalm, Marie
AU - Olopade, Olufunmilayo I.
AU - Nussbaum, Robert L.
AU - Rebbeck, Timothy R.
AU - Nathanson, Katherine L.
AU - Domchek, Susan M.
AU - Lu, Karen H.
AU - Karlan, Beth Y.
AU - Walsh, Christine
AU - Lester, Jenny
AU - Hein, Alexander
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Fasching, Peter A.
AU - Lambrechts, Diether
AU - Van Nieuwenhuysen, Els
AU - Vergote, Ignace
AU - Lambrechts, Sandrina
AU - Dicks, Ed
AU - Doherty, Jennifer A.
AU - Wicklund, Kristine G.
AU - Rossing, Mary Anne
AU - Rudolph, Anja
AU - Chang-Claude, Jenny
AU - Wang-Gohrke, Shan
AU - Eilber, Ursula
AU - Moysich, Kirsten B.
AU - Odunsi, Kunle
AU - Sucheston, Lara
AU - Lele, Shashi
AU - Wilkens, Lynne R.
AU - Goodman, Marc T.
AU - Thompson, Pamela J.
AU - Shvetsov, Yurii B.
AU - Runnebaum, Ingo B.
AU - Dürst, Matthias
AU - Hillemanns, Peter
AU - Dörk, Thilo
AU - Antonenkova, Natalia
AU - Bogdanova, Natalia
AU - Leminen, Arto
AU - Pelttari, Liisa M.
AU - Butzow, Ralf
AU - Modugno, Francesmary
AU - Kelley, Joseph L.
AU - Edwards, Robert P.
AU - Ness, Roberta B.
AU - Du Bois, Andreas
AU - Heitz, Florian
AU - Schwaab, Ira
AU - Harter, Philipp
AU - Matsuo, Keitaro
AU - Hosono, Satoyo
AU - Orsulic, Sandra
AU - Jensen, Allan
AU - Kjaer, Susanne Kruger
AU - Hogdall, Estrid
AU - Hasmad, Hanis Nazihah
AU - Noor Azmi, Mat Adenan
AU - Teo, Soo Hwang
AU - Woo, Yin Ling
AU - Fridley, Brooke L.
AU - Goode, Ellen L.
AU - Cunningham, Julie M.
AU - Vierkant, Robert A.
AU - Bruinsma, Fiona
AU - Giles, Graham G.
AU - Liang, Dong
AU - Hildebrandt, Michelle A T
AU - Wu, Xifeng
AU - Levine, Douglas A.
AU - Bisogna, Maria
AU - Berchuck, Andrew
AU - Iversen, Edwin S.
AU - Schildkraut, Joellen M.
AU - Concannon, Patrick
AU - Weber, Rachel Palmieri
AU - Cramer, Daniel W.
AU - Terry, Kathryn L.
AU - Poole, Elizabeth M.
AU - Tworoger, Shelley S.
AU - Bandera, Elisa V.
AU - Orlow, Irene
AU - Olson, Sara H.
AU - Krakstad, Camilla
AU - Salvesen, Helga B.
AU - Tangen, Ingvild L.
AU - Bjorge, Line
AU - Van Altena, Anne M.
AU - Aben, Katja K H
AU - Kiemeney, Lambertus A.
AU - Massuger, Leon F A G
AU - Kellar, Melissa
AU - Brooks-Wilson, Angela
AU - Kelemen, Linda E.
AU - Cook, Linda S.
AU - Le, Nhu D.
AU - Cybulski, Cezary
AU - Yang, Hannah
AU - Lissowska, Jolanta
AU - Brinton, Louise A.
AU - Wentzensen, Nicolas
AU - Hogdall, Claus
AU - Lundvall, Lene
AU - Nedergaard, Lotte
AU - Baker, Helen
AU - Song, Honglin
AU - Eccles, Diana
AU - McNeish, Ian
AU - Paul, James
AU - Carty, Karen
AU - Siddiqui, Nadeem
AU - Glasspool, Rosalind
AU - Whittemore, Alice S.
AU - Rothstein, Joseph H.
AU - McGuire, Valerie
AU - Sieh, Weiva
AU - Ji, Bu Tian
AU - Zheng, Wei
AU - Shu, Xiao Ou
AU - Gao, Yu Tang
AU - Rosen, Barry
AU - Risch, Harvey A.
AU - McLaughlin, John R.
AU - Narod, Steven A.
AU - Monteiro, Alvaro N.
AU - Chen, Ann
AU - Lin, Hui Yi
AU - Permuth-Wey, Jenny
AU - Sellers, Thomas A.
AU - Tsai, Ya Yu
AU - Chen, Zhihua
AU - Ziogas, Argyrios
AU - Anton-Culver, Hoda
AU - Gentry-Maharaj, Aleksandra
AU - Menon, Usha
AU - Harrington, Patricia
AU - Lee, Alice W.
AU - Wu, Anna H.
AU - Pearce, Celeste L.
AU - Coetzee, Gerry
AU - Pike, Malcolm C.
AU - Dansonka-Mieszkowska, Agnieszka
AU - Timorek, Agnieszka
AU - Rzepecka, Iwona K.
AU - Kupryjanczyk, Jolanta
AU - Freedman, Matt
AU - Noushmehr, Houtan
AU - Easton, Douglas F.
AU - Offit, Kenneth
AU - Couch, Fergus J.
AU - Gayther, Simon
AU - Pharoah, Paul P.
AU - Antoniou, Antonis C.
AU - Chenevix-Trench, Georgia
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
AB - 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 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
UR - http://www.scopus.com/inward/record.url?scp=84929171835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929171835&partnerID=8YFLogxK
U2 - 10.1038/ng.3185
DO - 10.1038/ng.3185
M3 - Article
AN - SCOPUS:84929171835
VL - 47
SP - 164
EP - 171
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 2
ER -