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

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

AU - KConFab Investigators

PY - 2020/6

Y1 - 2020/6

N2 - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. 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 < 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.

AB - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. 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 < 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.

KW - BRCA1 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Linkage Disequilibrium

KW - Mutation

KW - Triple Negative Breast Neoplasms/genetics

U2 - 10.1038/s41588-020-0609-2

DO - 10.1038/s41588-020-0609-2

M3 - SCORING: Journal article

C2 - 32424353

VL - 52

SP - 572

EP - 581

JO - NAT GENET

JF - NAT GENET

SN - 1061-4036

IS - 6

ER -