University of Oulu

Zhang, H., Ahearn, T.U., Lecarpentier, J. et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet 52, 572–581 (2020). https://doi.org/10.1038/s41588-020-0609-2

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

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Author: Zhang, Haoyu1,2; Ahearn, Thomas U.1; Lecarpentier, Julie3;
Barnes, Daniel3; Beesley, Jonathan4; Qi, Guanghao2; Hang, Xia5; O'Mara, Tracy A.4; Zhao, Ni2; Bolla, Manjeet K.6; Dunning, Alison M.3; Dennis, Joe6; Wang, Qin6; Abu Ful, Zumuruda7,8; Aittomaki, Kristiina9; Andrulis, Irene L.10; Anton-Culver, Hoda11; Arndt, Volker12; Aronson, Kristan J.13,14; Arun, Banu K.15; Auer, Paul L.16,17; Azzollini, Jacopo18; Barrowdale, Daniel19; Becher, Heiko20; Beckmann, Matthias W.21; Behrens, Sabine22; Benitez, Javier23; Bermisheva, Marina24; Bialkowska, Katarzyna25; Blanco, Ana26,27,28; Blomqvist, Carl29,30; Bogdanova, Natalia, V31,32,33; Bojesen, Stig E.34,35,36,37; Bonanni, Bernardo38; Bondavalli, Davide38; Borg, Ake39,40; Brauch, Hiltrud41,42,43; Brenner, Hermann12,43,44,45; Briceno, Ignacio46; Broeks, Annegien47; Brucker, Sara Y.48; Bruening, Thomas49; Burwinkel, Barbara50,51; Buys, Saundra S.52; Byers, Helen53; Caldes, Trinidad54; Caligo, Maria A.55; Calvello, Mariarosaria38; Campa, Daniele22,56; Castelao, Jose E.57; Chang-Claude, Jenny22,58; Chanock, Stephen J.1; Christiaens, Melissa59; Christiansen, Hans33; Chung, Wendy K.60,61; Claes, Kathleen B. M.62; Clarke, Christine L.63; Cornelissen, Sten47; Couch, Fergus J.64; Cox, Angela65; Cross, Simon S.66; Czene, Kamila67; Daly, Mary B.68; Devilee, Peter69; Diez, Orland70; Domchek, Susan M.71; Doerk, Thilo32; Dwek, Miriam72; Eccles, Diana M.73; Ekici, Arif B.74; Evans, D. Gareth53,75; Fasching, Peter A.21,76; Figueroa, Jonine77; Foretova, Lenka78; Fostira, Florentia79; Friedman, Eitan80; Frost, Debra19; Gago-Dominguez, Manuela81,82; Gapstur, Susan M.83; Garber, Judy84; Garcia-Saenz, Jose A.54; Gaudet, Mia M.83; Gayther, Simon A.85,86; Giles, Graham G.87,88,89; Godwin, Andrew K.90; Goldberg, Mark S.91,92,93; Goldgar, David E.94; Gonzalez-Neira, Anna37; Greene, Mark H.42; Gronwald, Jacek25; Guenel, Pascal95; Haeberle, Lothar96; Hahnen, Eric97,98; Haiman, Christopher A.99; Hake, Christopher R.100; Hall, Per67,101; Hamann, Ute102; Harkness, Elaine F.103,104; Heemskerk-Gerritsen, Bernadette A. M.105; Hillemanns, Peter32; Hogervorst, Frans B. L.106; Holleczek, Bernd107; Hollestelle, Antoinette105; Hooning, Maartje J.105; Hoover, Robert N.1; Hopper, John L.88; Howell, Anthony108; Huebner, Hanna21; Hulick, Peter J.109; Imyanitov, Evgeny N.110; Isaacs, Claudine111; Izatt, Louise112; Jager, Agnes105; Jakimovska, Milena113; Jakubowska, Anna25,114; James, Paul115; Janavicius, Ramunas116,117; Janni, Wolfgang118; John, Esther M.119; Jones, Michael E.120; Jung, Audrey22; Kaaks, Rudolf22; Kapoor, Pooja Middha22,121; Karlan, Beth Y.122; Keeman, Renske47; Khan, Sofia123; Khusnutdinova, Elza24,124; Kitahara, Cari M.125; Ko, Yon-Dschun126; Konstantopoulou, Irene79; Koppert, Linetta B.127; Koutros, Stella1; Kristensen, Vessela N.128,129; Laenkholm, Anne-Vibeke130; Lambrechts, Diether131,132; Larsson, Susanna C.133,134; Laurent-Puig, Pierre135; Lazaro, Conxi136; Lazarova, Emilija137; Lejbkowicz, Flavio7,8; Leslie, Goska6; Lesueur, Fabienne138; Lindblom, Annika139,140; Lissowska, Jolanta141; Lo, Wing-Yee41,142; Loud, Jennifer T.143; Lubinski, Jan25; Lukomska, Alicja25; Maclnnis, Robert J.87,88; Mannermaa, Arto144,145,146; Manoochehri, Mehdi102; Manoukian, Siranoush18; Margolin, Sara101,147; Martinez, Maria Elena82,148; Matricardi, Laura149; McGuffog, Lesley6; McLean, Catriona150; Mebirouk, Noura151; Meindl, Alfons152; Menon, Usha153; Miller, Austin154; Mingazheva, Elvira124; Montagna, Marco149; Mulligan, Anna Marie155,156; Mulot, Claire135; Muranen, Taru A.123; Nathanson, Katherine L.71; Neuhausen, Susan L.157; Nevanlinna, Heli123; Neven, Patrick59; Newman, William G.53,75; Nielsens, Finn C.158; Nikitina-Zake, Liene159; Nodora, Jesse82,160; Offit, Kenneth161; Olah, Edith162; Olopade, Olufunmilayo, I163,164; Olsson, Hakan165,166; Orr, Nick167; Papi, Laura168; Papp, Janos162; Park-Simon, Tjoung-Won32; Parsons, Michael T.4; Peissel, Bernard18; Peixoto, Ana169; Peshkin, Beth170; Peterlongo, Paolo171; Peto, Julian6,172; Phillips, Kelly-Anne88,173,174; Piedmonte, Marion154; Plaseska-Karanfilska, Dijana113; Prajzendanc, Karolina25; Prentice, Ross16; Prokofyeva, Darya20; Rack, Brigitte118; Radice, Paolo175; Ramus, Susan J.176,177,178; Rantala, Johanna179; Rashid, Muhammad U.102,180; Rennert, Gad7,8; Rennert, Hedy S.7,8; Risch, Harvey A.181; Romero, Atocha182,183; Rookus, Matti A.184; Ruebner, Matthias96; Ruediger, Thomas185; Saloustros, Emmanouil186; Sampson, Sarah187,188; Sandler, Dale P.189; Sawyer, Elinor J.190; Scheuner, Maren T.191; Schmutzler, Rita K.97,98; Schneeweiss, Andreas51,192,193; Schoemaker, Minouk J.120; Schoettker, Ben12; Schuermann, Peter32; Senter, Leigha194; Sharma, Priyanka195; Sherman, Mark E.196; Shu, Xiao-Ou197; Singer, Christian F.198,199; Smichkoska, Snezhana137; Soucy, Penny200; Southey, Melissa C.89; Spinelli, John J.201,202; Stone, Jennifer88,203,204; Stoppa-Lyonnet, Dominique205; Swerdlow, Anthony J.120,206; Szabo, Csilla, I207; Tamimi, Rulla M.5,208,209,210; Tapper, William J.211; Taylor, Jack A.189,212; Teixeira, Manuel R.169,183; Terry, MaryBeth213; Thomassen, Mads214; Thull, Darcy L.215; Tischkowitz, Marc216,217; Toland, Amanda E.218; Tollenaar, Rob A. E. M.219; Tomlinson, Ian220,221,222; Torres, Diana102,223; Troester, Melissa A.224,225; Truong, Therese95; Tung, Nadine226; Untch, Michael227; Vachon, Celine M.228; van den Ouweland, Ans M. W.229; van der Kolk, Lizet E.106; van Veen, Elke M.53,75; vanRensburg, Elizabeth J.230; Vega, Ana26,27,28; Wappenschmidt, Barbara97,98; Weinberg, Clarice R.231; Weitzel, Jeffrey N.232; Wildiers, Hans59; Winqvist, Robert233,234,235,236; Wolk, Alicja114,133,134; Yang, Xiaohong R.1; Yannoukakos, Drakoulis79; Zheng, Wei197; Zorn, Kristin K.237; Milne, Roger L.87,88,89; Kraft, Peter5,210; Simard, Jacques200; Pharoah, Paul D. P.3,6; Michailidou, Kyriaki6,238,239; Antoniou, Antonis C.6; Schmidt, Marjanka K.47,240; Chenevix-Trench, Georgia4; Easton, Douglas F.3; Chatterjee, Nilanjan2,241; Garcia-Closas, Montserrat1
Organizations: 1NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA.
2Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA.
3Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England.
4QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia.
5Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.
6Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.
7Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa, Israel.
8Technion Fac Med, Haifa, Israel.
9Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland.
10Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.
11Univ Calif Irvine, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA USA.
12German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
13Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada.
14Queens Univ, Canc Res Inst, Kingston, ON, Canada.
15Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA.
16Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.
17Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA.
18Fdn IRCCS Ist Nazl Tumori INT, Dept Med Oncol & Hematol, Unit Med Genet, Milan, Italy.
19Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England.
20Univ Med Ctr Hamburg Eppendorf, Inst Med Biometry & Epidemiol, Hamburg, Germany.
21Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany.
22DKFZ, Div Canc Epidemiol, Heidelberg, Germany.
23Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain.
24Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa, Russia.
25Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.
26Fdn Publ Galega Med Xen, Mol Med Unit, Santiago De Compostela, Spain.
27Complejo Hosp Univ Santiago, Inst Invest Sanitaria Santiago de Compostela IDIS, Serv Galego Saude SERGAS, Santiago De Compostela, Spain.
28CIBERER, Santiago De Compostela, Spain.
29Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.
30Orebro Univ Hosp, Dept Oncol, Orebro, Sweden.
31NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS.
32Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
33Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany.
34Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.
35Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.
36Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
37Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain.
38European Inst Oncol IEO IRCCS, Div Canc Prevent & Genet, Milan, Italy.
39Lund Univ, Dept Oncol, Lund, Sweden.
40Skane Univ Hosp, Lund, Sweden.
41Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.
42Univ Tubingen, iFIT Cluster Excellence, Tubingen, Germany.
43DKFZ, German Canc Consortium DKTK, Heidelberg, Germany.
44DKFZ, Div Prevent Oncol, Heidelberg, Germany.
45Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
46Univ Sabana, Fac Med, Biosci Dept, Chia, Colombia.
47Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands.
48Univ Tubingen, Dept Womens Hlth, Tubingen, Germany.
49Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accid In, Bochum, Germany.
50DKFZ, Mol Epidemiol Grp C080, Heidelberg, Germany.
51Heidelberg Univ, Univ Womens Clin Heidelberg, Mol Biol Breast Canc, Heidelberg, Germany.
52Huntsman Canc Inst, Dept Med, Salt Lake City, UT USA.
53Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med,Manchester NIHR Biomed R, Manchester, Lancs, England.
54Hosp Clin San Carlos, Ctr Invest Biomed Red Canc CIBERONC, Inst Invest Sanitaria San Carlos IdISSC, Med Oncol Dept, Madrid, Spain.
55Univ Hosp Pisa, Dept Lab Med, Sect Mol Genet, Pisa, Italy.
56Univ Pisa, Dept Biol, Pisa, Italy.
57Xerencia Xest Integrada Vigo SERGAS, Oncol & Genet Unit, Inst Invest Sanitaria Galicia IISGS, Vigo, Spain.
58Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, Hamburg, Germany.
59Univ Hosp Leuven, Leuven Multidisciplinary Breast Ctr, Leuven Canc Inst, Dept Oncol, Leuven, Belgium.
60Columbia Univ, Dept Pediat, New York, NY 10027 USA.
61Columbia Univ, Dept Med, New York, NY USA.
62Univ Ghent, Ctr Med Genet, Ghent, Belgium.
63Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
64Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
65Univ Sheffield, Sheffield Inst Nucle Acids SInFoNiA, Dept Oncol & Metab, Sheffield, S Yorkshire, England.
66Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England.
67Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
68Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA.
69Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands.
70Vall dHebron Inst Oncol VHIO, Oncogenet Grp, Barcelona, Spain.
71Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA.
72Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England.
73Univ Southampton, Canc Sci Acad Unit, Fac Med, Southampton, Hants, England.
74Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Inst Human Genet, Erlangen, Germany.
75Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Biol Sci,Div Evolut & Genom Med, Manchester, Lancs, England.
76Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA.
77Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Med Sch, Edinburgh, Midlothian, Scotland.
78Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
79Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, INRASTES, Athens, Greece.
80Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Ramat Gan, Israel.
81Complejo Hosp Univ Santiago, Galician Fdn Genom Med, SERGAS, IDIS,Genom Med Grp, Santiago De Compostela, Spain.
82Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
83Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA.
84Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA.
85Cedars Sinai Med Ctr, Ctr Bioinformat & Funct Genom, Los Angeles, CA 90048 USA.
86Cedars Sinai Med Ctr, Cedars Sinai Genom Core, Los Angeles, CA 90048 USA.
87Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.
88Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
89Monash Univ, Sch Clin Sci Monash Hlth, Precis Med, Melbourne, Vic, Australia.
90Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA.
91McGill Univ, Dept Med, Montreal, PQ, Canada.
92McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada.
93Univ Malaya, Canc Res Inst, Breast Canc Res Unit, Med Ctr, Kuala Lumpur, Malaysia.
94Univ Utah, Huntsman Canc Inst, Dept Dermatol, Sch Med, Salt Lake City, UT USA.
95Univ Paris Sud, Univ Paris Saclay, Ctr Res Epidemiol & Populat Hlth CESP, INSERM, Paris, France.
96Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynaecol & Obstet, Erlangen, Germany.
97Univ Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, Ctr Integrated Oncol CIO, Cologne, Germany.
98Univ Cologne, Univ Hosp Cologne, Cologne, Germany.
99Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90007 USA.
100Waukesha Mem Hosp Pro Hlth Care, Waukesha, WI USA.
101Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.
102DKFZ, Mol Genet Breast Canc, Heidelberg, Germany.
103Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Div Informat Imaging & Data Sci, Manchester, Lancs, England.
104Manchester Univ NHS Fdn Trust, Wythenshawe Hosp, Nightingale Breast Screening Ctr, Manchester, Lancs, England.
105Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
106Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands.
107Saarland Canc Registry, Saarbrucken, Germany.
108Univ Manchester, Div Canc Sci, Manchester, Lancs, England.
109NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA.
110NN Petrov Inst Oncol, St Petersburg, Russia.
111Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA.
112Guys & St Thomas NHS Fdn Trust, Clin Genet, London, England.
113Macedonian Acad Sci & Arts, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje, North Macedonia.
114Pomeranian Med Univ, Independent Lab Mol Biol & Genet Diagnost, Szczecin, Poland.
115Peter MacCallum Canc Ctr, Parkville Familial Canc Ctr, Melbourne, Vic, Australia.
116Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, Vilnius, Lithuania.
117State Res Inst Ctr Innovat Med, Vilnius, Lithuania.
118Univ Hosp Ulm, Dept Gynaecol & Obstet, Ulm, Germany.
119Stanford Univ, Sch Med, Stanford Canc Inst, Dept Med,Div Oncol, Stanford, CA 94305 USA.
120Inst Canc Res, Div Genet & Epidemiol, London, England.
121Heidelberg Univ, Fac Med, Heidelberg, Germany.
122Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA.
123Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland.
124Bashkir State Med Univ, Dept Genet & Fundamental Med, Ufa, Russia.
125NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
126Johanniter Krankenhaus, Dept Internal Med, Evangel Kliniken Bonn, Bonn, Germany.
127Erasmus MC Canc Inst, Dept Surg Oncol, Family Canc Clin, Rotterdam, Netherlands.
128Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
129Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
130Zealand Univ Hosp, Dept Surg Pathol, Slagelse, Denmark.
131VIB, VIB Ctr Canc Biol, Leuven, Belgium.
132Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.
133Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
134Uppsala Univ, Dept Surg Sci, Uppsala, Sweden.
135Univ Paris Sorbonne Cite, INSERM UMR S1147, Paris, France.
136CIBERONC, Catalan Inst Oncol ICO, Mol Diagnost Unit, Bellvitge Biomed Res Inst IDIBELL,Hereditary Canc, Barcelona, Spain.
137Ss Cyril & Methodius Univ Skopje, Univ Clin Radiotherapy & Oncol, Med Fac, Skopje, North Macedonia.
138INSERM U900, Genet Epidemiol Canc Team, Paris, France.
139Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
140Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.
141M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Oncol Inst, Warsaw, Poland.
142Univ Tubingen, Tubingen, Germany.
143NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
144Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.
145Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.
146Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, Kuopio, Finland.
147Karolinska Inst, Dept Clin Sci & Educ, Soder Sjukhuset, Stockholm, Sweden.
148Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
149Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy.
150Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia.
151PSL Univ, Inst Curie, Mines ParisTech, INSERM U900,Genet Epidemiol Canc Team, Paris, France.
152Ludwig Maximilian Univ Munich, Dept Gynecol & Obstet, Munich, Germany.
153UCL, Inst Clin Trials & Methodol, MRC Clin Trials Unit UCL, London, England.
154Roswell Park Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA.
155Univ Hlth Network, Lab Med Program, Toronto, ON, Canada.
156Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
157Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA.
158Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark.
159Latvian Biomed Res & Study Ctr, Riga, Latvia.
160University California San Diego, Sch Med, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
161Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA.
162Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary.
163Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA.
164Univ Melbourne, Dept Clin Pathol, Melbourne, Vic, Australia.
165Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden.
166Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA.
167Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland.
168Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy.
169Portuguese Oncol Inst, Dept Genet, Porto, Portugal.
170Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC USA.
171FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy.
172London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
173Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.
174Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia.
175INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Res, Milan, Italy.
176Univ NSW Sydney, Lowy Canc Res Ctr, Adult Canc Program, Sydney, NSW, Australia.
177Univ NSW Sydney, Fac Med, Sch Womens & Childrens Hlth, Sydney, NSW, Australia.
178Garvan Inst Med Res, Kinghorn Canc Ctr, Sydney, NSW, Australia.
179Karolinska Inst, Clin Genet, Stockholm, Sweden.
180Shaukat Khanum Mem Canc Hosp & Res Ctr SKMCH&RC, Dept Basic Sci, Lahore, Pakistan.
181Yale Sch Publ Hlth, Chron Dis Epidemiol, New Haven, CT USA.
182Hosp Univ Puerta de Hierro, Med Oncol Dept, Madrid, Spain.
183Univ Porto, Biomed Sci Inst ICBAS, Porto, Portugal.
184Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands.
185Staedt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany.
186Univ Hosp Larissa, Dept Oncol, Larisa, Greece.
187Manchester Univ NHS Fdn Trust, Prevent Breast Canc Ctr, Manchester, Lancs, England.
188Manchester Univ NHS Fdn Trust, Nightingale Breast Screening Ctr, Manchester, Lancs, England.
189NIEHS, Epidemiol Branch, NIH, Durham, NC USA.
190Guys Hosp, Kings Coll London, Res Oncol, London, England.
191Univ Calif San Francisco, Canc Genet & Prevent Program, San Francisco, CA 94143 USA.
192Univ Hosp, NCT, Heidelberg, Germany.
193DKFZ, Heidelberg, Germany.
194Ohio State Univ, Comprehens Canc Ctr, Dept Internal Med, Div Human Genet,Clin Canc Genet Program, Columbus, OH 43210 USA.
195Univ Kansas, Med Ctr, Dept Internal Med, Div Oncol, Kansas City, KS 66103 USA.
196Mayo Clin, Dept Hlth Sci Res, Coll Med, Jacksonville, FL 32224 USA.
197Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Dept Med,Sch Med,Div Epidemiol, Nashville, TN 37212 USA.
198Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria.
199Med Univ Vienna, Comprehens Canc Ctr, Vienna, Austria.
200Univ Laval, Ctr Hosp Univ Quebec, Genom Ctr, Res Ctr, Quebec City, PQ, Canada.
201BC Canc, Populat Oncol, Vancouver, BC, Canada.
202Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
203Curtin Univ, Curtin UWA Ctr Genet Origins Hlth & Dis, Perth, WA, Australia.
204Univ Western Australia, Perth, WA, Australia.
205Paris Descartes Sorbonne Paris Cite Univ, Dept Genet, INSERM U830, Inst Curie, Paris, France.
206Inst Canc Res, Div Breast Canc Res, London, England.
207NCI, NHGRI, Bethesda, MD 20892 USA.
208Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
209Harvard Med Sch, Boston, MA 02115 USA.
210Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
211Univ Southampton, Fac Med, Southampton, Hants, England.
212NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Durham, NC USA.
213Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.
214Odense Univ Hosp, Dept Clin Genet, Odense, Denmark.
215Univ Pittsburgh, Magee Womens Hosp, Sch Med, Dept Med, Pittsburgh, PA 15213 USA.
216McGill Univ, Dept Human Genet & Oncol, Program Canc Genet, Montreal, PQ, Canada.
217Univ Cambridge, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Dept Med Genet, Cambridge, England.
218Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA.
219Leiden Univ, Dept Surg, Med Ctr, Leiden, Netherlands.
220Univ Birmingham, Inst Canc & Genom Sci, Birmingham, W Midlands, England.
221Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
222Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England.
223Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia.
224Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA.
225Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA.
226Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA.
227Helios Clin Berlin Buch, Dept Gynecol & Obstet, Berlin, Germany.
228Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA.
229Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands.
230Univ Pretoria, Dept Genet, Pretoria, South Africa.
231NIEHS, Biostat & Computat Biol Branch, NIH, Durham, NC USA.
232City Hope Natl Med Ctr, Clin Canc Genom, Duarte, CA USA.
233Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.
234Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland.
235Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
236Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands.
237Univ Pittsburgh, Magee Womens Hosp, Sch Med, Pittsburgh, PA 15213 USA.
238Cyprus Inst Neurol & Genet, Biostat Unit, Nicosia, Cyprus.
239Cyprus Sch Mol Med, Nicosia, Cyprus.
240Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands.
241Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA.
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2020070947186
Language: English
Published: Springer Nature, 2020
Publish Date: 2020-11-18
Description:

Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. 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 < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 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 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 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.

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Series: Nature genetics
ISSN: 1061-4036
ISSN-E: 1546-1718
ISSN-L: 1061-4036
Volume: 52
Issue: 6
Pages: 572 - 581
DOI: 10.1038/s41588-020-0609-2
OADOI: https://oadoi.org/10.1038/s41588-020-0609-2
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3111 Biomedicine
Subjects:
Funding: This project has been funded in part with Federal funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. Genotyping for the OncoArray was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l'Économie et de la Science et de l'Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1U19 CA148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea; 1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). Genotyping for the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Ministère de l'Économie, Innovation et Exportation du Québec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Combination of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative (1U19 CA148065) (DRIVE, part of the GAME-ON initiative). Linkage disequilibrium score regression analysis was supported by grant CA194393. BCAC was funded by Cancer Research UK (C1287/A16563) and by the European Union via its Seventh Framework Programme (HEALTH-F2-2009-223175; COGS) and the Horizon 2020 Research and Innovation Programme (633784 (B-CAST) and 634935 (BRIDGES)). CIMBA was funded by Cancer Research UK (C12292/A20861 and C12292/A11174). N.C. was funded by NHGRI (1R01 HG010480-01). For a full description of funding and acknowledgments, see the Supplementary Note.
Copyright information: © 2020, Springer Nature. This is a post-peer-review, pre-copyedit version of an article published in Nature Genetics. The final authenticated version is available online at: https://doi.org/10.1038/s41588-020-0609-2