Abstract
| Original language | English |
|---|---|
| Journal | Nature Genetics |
| Issue number | 6 |
| Publication status | Published - Jun 1 2020 |
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Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. / Zhang, Haoyu; Ahearn, Thomas U.; Lecarpentier, Julie et al.
In: Nature Genetics, No. 6, 01.06.2020.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
AU - Zhang, Haoyu
AU - Ahearn, Thomas U.
AU - Lecarpentier, Julie
AU - Barnes, Daniel
AU - Beesley, Jonathan
AU - Qi, Guanghao
AU - Jiang, Xia
AU - O'Mara, Tracy A.
AU - Zhao, Ni
AU - Bolla, Manjeet K.
AU - Dunning, Alison M.
AU - Dennis, Joe
AU - Wang, Qin
AU - Ful, Zumuruda Abu
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L.
AU - Anton-Culver, Hoda
AU - Arndt, Volker
AU - Aronson, Kristan J.
AU - Arun, Banu K.
AU - Auer, Paul L.
AU - Azzollini, Jacopo
AU - Barrowdale, Daniel
AU - Becher, Heiko
AU - Beckmann, Matthias W.
AU - Behrens, Sabine
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Bialkowska, Katarzyna
AU - Blanco, Ana
AU - Blomqvist, Carl
AU - Bogdanova, Natalia V.
AU - Bojesen, Stig E.
AU - Bonanni, Bernardo
AU - Bondavalli, Davide
AU - Borg, Ake
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Briceno, Ignacio
AU - Broeks, Annegien
AU - Brucker, Sara Y.
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Buys, Saundra S.
AU - Byers, Helen
AU - Caldés, Trinidad
AU - Caligo, Maria A.
AU - Calvello, Mariarosaria
AU - Campa, Daniele
AU - Castelao, Jose E.
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Christiaens, Melissa
AU - Christiansen, Hans
AU - Chung, Wendy K.
AU - Claes, Kathleen B. M.
AU - Clarke, Christine L.
AU - Cornelissen, Sten
AU - Couch, Fergus J.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Czene, Kamila
AU - Daly, Mary B.
AU - Devilee, Peter
AU - Diez, Orland
AU - Domchek, Susan M.
AU - Dörk, Thilo
AU - Dwek, Miriam
AU - Eccles, Diana M.
AU - Ekici, Arif B.
AU - Evans, D. Gareth
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Foretova, Lenka
AU - Fostira, Florentia
AU - Friedman, Eitan
AU - Frost, Debra
AU - Gago-Dominguez, Manuela
AU - Gapstur, Susan M.
AU - Garber, Judy
AU - García-Sáenz, José A.
AU - Gaudet, Mia M.
AU - Gayther, Simon A.
AU - Giles, Graham G.
AU - Godwin, Andrew K.
AU - Goldberg, Mark S.
AU - Goldgar, David E.
AU - González-Neira, Anna
AU - Greene, Mark H.
AU - Gronwald, Jacek
AU - Guénel, Pascal
AU - Häberle, Lothar
AU - Hahnen, Eric
AU - Haiman, Christopher A.
AU - Hake, Christopher R.
AU - Hall, Per
AU - Hamann, Ute
AU - Harkness, Elaine F.
AU - Heemskerk-Gerritsen, Bernadette A. M.
AU - Hillemanns, Peter
AU - Hogervorst, Frans B. L.
AU - Holleczek, Bernd
AU - Hollestelle, Antoinette
AU - Hooning, Maartje J.
AU - Hoover, Robert N.
AU - Hopper, John L.
AU - Howell, Anthony
AU - Huebner, Hanna
AU - Hulick, Peter J.
AU - Imyanitov, Evgeny N.
AU - Isaacs, Claudine
AU - Izatt, Louise
AU - Jager, Agnes
AU - Jakimovska, Milena
AU - Jakubowska, Anna
AU - James, Paul
AU - Janavicius, Ramunas
AU - Janni, Wolfgang
AU - John, Esther M.
AU - Jones, Michael E.
AU - Jung, Audrey
AU - Kaaks, Rudolf
AU - Kapoor, Pooja Middha
AU - Karlan, Beth Y.
AU - Keeman, Renske
AU - Khan, Sofia
AU - Khusnutdinova, Elza
AU - Kitahara, Cari M.
AU - Ko, Yon-Dschun
AU - Konstantopoulou, Irene
AU - Koppert, Linetta B.
AU - Koutros, Stella
AU - Kristensen, Vessela N.
AU - Laenkholm, Anne-Vibeke
AU - Lambrechts, Diether
AU - Larsson, Susanna C.
AU - Laurent-Puig, Pierre
AU - Lazaro, Conxi
AU - Lazarova, Emilija
AU - Lejbkowicz, Flavio
AU - Leslie, Goska
AU - Lesueur, Fabienne
AU - Lindblom, Annika
AU - Lissowska, Jolanta
AU - Lo, Wing-Yee
AU - Loud, Jennifer T.
AU - Lubinski, Jan
AU - Lukomska, Alicja
AU - MacInnis, Robert J.
AU - Mannermaa, Arto
AU - Manoochehri, Mehdi
AU - Manoukian, Siranoush
AU - Margolin, Sara
AU - Martinez, Maria Elena
AU - Matricardi, Laura
AU - McGuffog, Lesley
AU - McLean, Catriona
AU - Mebirouk, Noura
AU - Meindl, Alfons
AU - Menon, Usha
AU - Miller, Austin
AU - Mingazheva, Elvira
AU - Montagna, Marco
AU - Mulligan, Anna Marie
AU - Mulot, Claire
AU - Muranen, Taru A.
AU - Nathanson, Katherine L.
AU - Neuhausen, Susan L.
AU - Nevanlinna, Heli
AU - Neven, Patrick
AU - Newman, William G.
AU - Nielsen, Finn C.
AU - Nikitina-Zake, Liene
AU - Nodora, Jesse
AU - Offit, Kenneth
AU - Olah, Edith
AU - Olopade, Olufunmilayo I.
AU - Olsson, Håkan
AU - Orr, Nick
AU - Papi, Laura
AU - Papp, Janos
AU - Park-Simon, Tjoung-Won
AU - Parsons, Michael T.
AU - Peissel, Bernard
AU - Peixoto, Ana
AU - Peshkin, Beth
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Phillips, Kelly-Anne
AU - Piedmonte, Marion
AU - Plaseska-Karanfilska, Dijana
AU - Prajzendanc, Karolina
AU - Prentice, Ross
AU - Prokofyeva, Darya
AU - Rack, Brigitte
AU - Radice, Paolo
AU - Ramus, Susan J.
AU - Rantala, Johanna
AU - Rashid, Muhammad U.
AU - Rennert, Gad
AU - Rennert, Hedy S.
AU - Risch, Harvey A.
AU - Romero, Atocha
AU - Rookus, Matti A.
AU - Rübner, Matthias
AU - Rüdiger, Thomas
AU - Saloustros, Emmanouil
AU - Sampson, Sarah
AU - Sandler, Dale P.
AU - Sawyer, Elinor J.
AU - Scheuner, Maren T.
AU - Schmutzler, Rita K.
AU - Schneeweiss, Andreas
AU - Schoemaker, Minouk J.
AU - Schöttker, Ben
AU - Schürmann, Peter
AU - Senter, Leigha
AU - Sharma, Priyanka
AU - Sherman, Mark E.
AU - Shu, Xiao-Ou
AU - Singer, Christian F.
AU - Smichkoska, Snezhana
AU - Soucy, Penny
AU - Southey, Melissa C.
AU - Spinelli, John J.
AU - Stone, Jennifer
AU - Stoppa-Lyonnet, Dominique
AU - Swerdlow, Anthony J.
AU - Szabo, Csilla I.
AU - Tamimi, Rulla M.
AU - Tapper, William J.
AU - Taylor, Jack A.
AU - Teixeira, Manuel R.
AU - Terry, MaryBeth
AU - Thomassen, Mads
AU - Thull, Darcy L.
AU - Tischkowitz, Marc
AU - Toland, Amanda E.
AU - Tollenaar, Rob A. E. M.
AU - Tomlinson, Ian
AU - Torres, Diana
AU - Troester, Melissa A.
AU - Truong, Thérèse
AU - Tung, Nadine
AU - Untch, Michael
AU - Vachon, Celine M.
AU - van den Ouweland, Ans M. W.
AU - van der Kolk, Lizet E.
AU - van Veen, Elke M.
AU - vanRensburg, Elizabeth J.
AU - Vega, Ana
AU - Wappenschmidt, Barbara
AU - Weinberg, Clarice R.
AU - Weitzel, Jeffrey N.
AU - Wildiers, Hans
AU - Winqvist, Robert
AU - Wolk, Alicja
AU - Yang, Xiaohong R.
AU - Yannoukakos, Drakoulis
AU - Zheng, Wei
AU - Zorn, Kristin K.
AU - Milne, Roger L.
AU - Kraft, Peter
AU - Simard, Jacques
AU - Pharoah, Paul D. P.
AU - Michailidou, Kyriaki
AU - Antoniou, Antonis C.
AU - Schmidt, Marjanka K.
AU - Chenevix-Trench, Georgia
AU - Easton, Douglas F.
AU - Chatterjee, Nilanjan
AU - García-Closas, Montserrat
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P textless 5.0 × 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate textless 0.05). Five loci showed associations (P textless 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2like disease and 37.6negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
AB - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P textless 5.0 × 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate textless 0.05). Five loci showed associations (P textless 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2like disease and 37.6negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
M3 - Article
SN - 1061-4036
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -