Abstract
Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
| Original language | English (US) |
|---|---|
| Journal | Journal of the National Cancer Institute |
| Volume | 107 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2015 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Prediction of breast cancer risk based on profiling with common genetic variants. / Mavaddat, Nasim; Pharoah, Paul D.P.; Michailidou, Kyriaki; Tyrer, Jonathan; Brook, Mark N.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Brown, Judith; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Peto, Julian; Dos-Santos-Silva, Isabel; Dudbridge, Frank; Johnson, Nichola; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Rutgers, Emiel J.; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Figueroa, Jonine; Chanock, Stephen J.; Brinton, Louise; Lissowska, Jolanta; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Pankratz, Vernon S.; Lambrechts, Diether; Wildiers, Hans; Van Ongeval, Chantal; Van Limbergen, Erik; Kristensen, Vessela; Grenaker Alnæs, Grethe; Nord, Silje; Borresen-Dale, Anne Lise; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Trentham-Dietz, Amy; Newcomb, Polly; Titus, Linda; Egan, Kathleen M.; Hunter, David J.; Lindstrom, Sara; Tamimi, Rulla M.; Kraft, Peter; Rahman, Nazneen; Turnbull, Clare; Renwick, Anthony; Seal, Sheila; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Benitez, Javier; Pilar Zamora, M.; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Dörk, Thilo; Anton-Culver, Hoda; Neuhausen, Susan L.; Ziogas, Argyrios; Bernstein, Leslie; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Van Asperen, Christi J.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Khusnutdinova, Elza; Bermisheva, Marina; Prokofyeva, Darya; Takhirova, Zalina; Meindl, Alfons; Schmutzler, Rita K.; Sutter, Christian; Yang, Rongxi; Schürmann, Peter; Bremer, Michael; Christiansen, Hans; Park-Simon, Tjoung Won; Hillemanns, Peter; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Pensotti, Valeria; Hopper, John L.; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C.; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon Dschun; Sigurdson, Alice J.; Doody, Michele M.; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Försti, Asta; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Marie Mulligan, Anna; Chenevix-Trench, Georgia; Balleine, Rosemary; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Lindblom, Annika; Margolin, Sara; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Eilber, Ursula; Wang-Gohrke, Shan; Hooning, Maartje J.; Hollestelle, Antoinette; Van Den Ouweland, Ans M.W.; Koppert, Linetta B.; Carpenter, Jane; Clarke, Christine; Scott, Rodney; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli Matti; Hartikainen, Jaana M.; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Karina Dieffenbach, Aida; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Offit, Kenneth; Vijai, Joseph; Robson, Mark; Rau-Murthy, Rohini; Dwek, Miriam; Swann, Ruth; Annie Perkins, Katherine; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Eccles, Diana M.; Tapper, William J.; Rafiq, Sajjad; John, Esther M.; Whittemore, Alice S.; Slager, Susan; Yannoukakos, Drakoulis; Toland, Amanda E.; Yao, Song; Zheng, Wei; Halverson, Sandra L.; González-Neira, Anna; Pita, Guillermo; Rosario Alonso, M.; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; Simard, Jacques; Hall, Per; Easton, Douglas F.; Garcia-Closas, Montserrat.
In: Journal of the National Cancer Institute, Vol. 107, No. 5, 01.05.2015.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Prediction of breast cancer risk based on profiling with common genetic variants
AU - Mavaddat, Nasim
AU - Pharoah, Paul D.P.
AU - Michailidou, Kyriaki
AU - Tyrer, Jonathan
AU - Brook, Mark N.
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dennis, Joe
AU - Dunning, Alison M.
AU - Shah, Mitul
AU - Luben, Robert
AU - Brown, Judith
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Peto, Julian
AU - Dos-Santos-Silva, Isabel
AU - Dudbridge, Frank
AU - Johnson, Nichola
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Verhoef, Senno
AU - Rutgers, Emiel J.
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Orr, Nick
AU - Schoemaker, Minouk J.
AU - Figueroa, Jonine
AU - Chanock, Stephen J.
AU - Brinton, Louise
AU - Lissowska, Jolanta
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Vachon, Celine
AU - Pankratz, Vernon S.
AU - Lambrechts, Diether
AU - Wildiers, Hans
AU - Van Ongeval, Chantal
AU - Van Limbergen, Erik
AU - Kristensen, Vessela
AU - Grenaker Alnæs, Grethe
AU - Nord, Silje
AU - Borresen-Dale, Anne Lise
AU - Nevanlinna, Heli
AU - Muranen, Taru A.
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Flesch-Janys, Dieter
AU - Fasching, Peter A.
AU - Haeberle, Lothar
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Schneeweiss, Andreas
AU - Sohn, Christof
AU - Trentham-Dietz, Amy
AU - Newcomb, Polly
AU - Titus, Linda
AU - Egan, Kathleen M.
AU - Hunter, David J.
AU - Lindstrom, Sara
AU - Tamimi, Rulla M.
AU - Kraft, Peter
AU - Rahman, Nazneen
AU - Turnbull, Clare
AU - Renwick, Anthony
AU - Seal, Sheila
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Humphreys, Keith
AU - Benitez, Javier
AU - Pilar Zamora, M.
AU - Arias Perez, Jose Ignacio
AU - Menéndez, Primitiva
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katarzyna
AU - Bogdanova, Natalia V.
AU - Antonenkova, Natalia N.
AU - Dörk, Thilo
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Ziogas, Argyrios
AU - Bernstein, Leslie
AU - Devilee, Peter
AU - Tollenaar, Robert A.E.M.
AU - Seynaeve, Caroline
AU - Van Asperen, Christi J.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Reed, Malcolm W.R.
AU - Khusnutdinova, Elza
AU - Bermisheva, Marina
AU - Prokofyeva, Darya
AU - Takhirova, Zalina
AU - Meindl, Alfons
AU - Schmutzler, Rita K.
AU - Sutter, Christian
AU - Yang, Rongxi
AU - Schürmann, Peter
AU - Bremer, Michael
AU - Christiansen, Hans
AU - Park-Simon, Tjoung Won
AU - Hillemanns, Peter
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Sanchez, Marie
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Manoukian, Siranoush
AU - Pensotti, Valeria
AU - Hopper, John L.
AU - Tsimiklis, Helen
AU - Apicella, Carmel
AU - Southey, Melissa C.
AU - Brauch, Hiltrud
AU - Brüning, Thomas
AU - Ko, Yon Dschun
AU - Sigurdson, Alice J.
AU - Doody, Michele M.
AU - Hamann, Ute
AU - Torres, Diana
AU - Ulmer, Hans Ulrich
AU - Försti, Asta
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Kerin, Michael J.
AU - Miller, Nicola
AU - Andrulis, Irene L.
AU - Knight, Julia A.
AU - Glendon, Gord
AU - Marie Mulligan, Anna
AU - Chenevix-Trench, Georgia
AU - Balleine, Rosemary
AU - Giles, Graham G.
AU - Milne, Roger L.
AU - McLean, Catriona
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Schumacher, Fredrick
AU - Le Marchand, Loic
AU - Eilber, Ursula
AU - Wang-Gohrke, Shan
AU - Hooning, Maartje J.
AU - Hollestelle, Antoinette
AU - Van Den Ouweland, Ans M.W.
AU - Koppert, Linetta B.
AU - Carpenter, Jane
AU - Clarke, Christine
AU - Scott, Rodney
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Brenner, Hermann
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Karina Dieffenbach, Aida
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Grip, Mervi
AU - Offit, Kenneth
AU - Vijai, Joseph
AU - Robson, Mark
AU - Rau-Murthy, Rohini
AU - Dwek, Miriam
AU - Swann, Ruth
AU - Annie Perkins, Katherine
AU - Goldberg, Mark S.
AU - Labrèche, France
AU - Dumont, Martine
AU - Eccles, Diana M.
AU - Tapper, William J.
AU - Rafiq, Sajjad
AU - John, Esther M.
AU - Whittemore, Alice S.
AU - Slager, Susan
AU - Yannoukakos, Drakoulis
AU - Toland, Amanda E.
AU - Yao, Song
AU - Zheng, Wei
AU - Halverson, Sandra L.
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Rosario Alonso, M.
AU - Álvarez, Nuria
AU - Herrero, Daniel
AU - Tessier, Daniel C.
AU - Vincent, Daniel
AU - Bacot, Francois
AU - Luccarini, Craig
AU - Baynes, Caroline
AU - Ahmed, Shahana
AU - Maranian, Mel
AU - Healey, Catherine S.
AU - Simard, Jacques
AU - Hall, Per
AU - Easton, Douglas F.
AU - Garcia-Closas, Montserrat
N1 - Publisher Copyright: © 2015 © The Author 2015. Published by Oxford University Press.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
AB - Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
UR - http://www.scopus.com/inward/record.url?scp=84928761946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928761946&partnerID=8YFLogxK
U2 - 10.1093/jnci/djv036
DO - 10.1093/jnci/djv036
M3 - Article
C2 - 25855707
AN - SCOPUS:84928761946
VL - 107
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 5
ER -