Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Karoline B. Kuchenbaecker; Lesley McGuffog; Daniel Barrowdale; Andrew Lee; Penny Soucy; Joe Dennis; Susan M. Domchek; Mark Robson; Amanda B. Spurdle; Susan J. Ramus; Nasim Mavaddat; Mary Beth Terry; Susan L. Neuhausen; Rita Katharina Schmutzler; Jacques Simard; Paul D.P. Pharoah; Kenneth Offit; Fergus J. Couch; Georgia Chenevix-Trench; Douglas F. Easton; Antonis C. Antoniou; Sue Healey; Michael Lush; Ute Hamann; Melissa Southey; Esther M. John; Wendy K. Chung; Mary B. Daly; Saundra S. Buys; David E. Goldgar; Cecilia M. Dorfling; Elizabeth J. van Rensburg; Yuan Chun Ding; Bent Ejlertsen; Anne Marie Gerdes; Thomas V.O. Hansen; Susan Slager; Emily Hallberg; Javier Benitez; Ana Osorio; Nancy Cohen; William Lawler; Jeffrey N. Weitzel; Paolo Peterlongo; Valeria Pensotti; Riccardo Dolcetti; Monica Barile; Bernardo Bonanni; Jacopo Azzollini; Siranoush Manoukian; Bernard Peissel; Paolo Radice; Antonella Savarese; Laura Papi; Giuseppe Giannini; Florentia Fostira; Irene Konstantopoulou; Julian Adlard; Carole Brewer; Jackie Cook; Rosemarie Davidson; Diana Eccles; Ros Eeles; Steve Ellis; EMBRACE; Debra Frost; Shirley Hodgson; Louise Izatt; Fiona Lalloo; Kai ren Ong; Andrew K. Godwin; Norbert Arnold; Bernd Dworniczak; Christoph Engel; Andrea Gehrig; Eric Hahnen; Jan Hauke; Karin Kast; Alfons Meindl; Dieter Niederacher; Raymonda Varon-Mateeva; Shan Wang-Gohrke; Barbara Wappenschmidt; Laure Barjhoux; Marie Agnès Collonge-Rame; Camille Elan; Study Collaborators GEMO Study Collaborators; Lisa Golmard; Emmanuelle Barouk-Simonet; Fabienne Lesueur; Sylvie Mazoyer; Joanna Sokolowska; Dominique StoppaLyonnet; Claudine Isaacs; Kathleen B.M. Claes; Bruce Poppe; Miguel de la Hoya; Vanesa Garcia-Barberan; Kristiina Aittomäki; Heli Nevanlinna; Margreet G.E.M. Ausems; J. L. de Lange; Encarna B. Gomez Garcia; HEBON; Frans B.L. Hogervorst; Carolien M. Kets; Hanne E.J. Meijers-Heijboer; Jan C. Oosterwijk; Matti A. Rookus; Christi J. van Asperen; Ans M.W. van den Ouweland; Helena C. van Doorn; Theo A.M. van Os; Ava Kwong; Edith Olah; Orland Diez; Joan Brunet; Conxi Lazaro; Alex Teulé; Jacek Gronwald; Anna Jakubowska; Katarzyna Kaczmarek; Jan Lubinski; Grzegorz Sukiennicki; Rosa B. Barkardottir; Jocelyne Chiquette; Simona Agata; Marco Montagna; Manuel R. Teixeira; KCon Fab Investigators; Sue Kyung Park; Curtis Olswold; Marc Tischkowitz; Lenka Foretova; Pragna Gaddam; Joseph Vijai; Georg Pfeiler; Christine Rappaport-Fuerhauser; Christian F. Singer; Muy Kheng M. Tea; Mark H. Greene; Jennifer T. Loud; Gad Rennert; Evgeny N. Imyanitov; Peter J. Hulick; John L. Hays; Marion Piedmonte; Gustavo C. Rodriguez; Julie Martyn; Gord Glendon; Anna Marie Mulligan; Irene L. Andrulis; Amanda Ewart Toland; Uffe Birk Jensen; Torben A. Kruse; Inge Sokilde Pedersen; Mads Thomassen; Maria A. Caligo; Soo Hwang Teo; Raanan Berger; Eitan Friedman; Yael Laitman; Brita Arver; Ake Borg; Hans Ehrencrona; Johanna Rantala; Olufunmilayo I. Olopade; Patricia A. Ganz; Robert L. Nussbaum; Angela R. Bradbury; Katherine L. Nathanson; Banu K. Arun; Paul James; Beth Y. Karlan; Jenny Lester

doi:10.1093/jnci/djw302

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Karoline B. Kuchenbaecker, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Penny Soucy, Joe Dennis, Susan M. Domchek, Mark Robson, Amanda B. Spurdle, Susan J. Ramus, Nasim Mavaddat, Mary Beth Terry, Susan L. Neuhausen, Rita Katharina Schmutzler, Jacques Simard, Paul D.P. Pharoah, Kenneth Offit, Fergus J. Couch, Georgia Chenevix-Trench, Douglas F. EastonAntonis C. Antoniou^*, Sue Healey, Michael Lush, Ute Hamann, Melissa Southey, Esther M. John, Wendy K. Chung, Mary B. Daly, Saundra S. Buys, David E. Goldgar, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Yuan Chun Ding, Bent Ejlertsen, Anne Marie Gerdes, Thomas V.O. Hansen, Susan Slager, Emily Hallberg, Javier Benitez, Ana Osorio, Nancy Cohen, William Lawler, Jeffrey N. Weitzel, Paolo Peterlongo, Valeria Pensotti, Riccardo Dolcetti, Monica Barile, Bernardo Bonanni, Jacopo Azzollini, Siranoush Manoukian, Bernard Peissel, Paolo Radice, Antonella Savarese, Laura Papi, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Julian Adlard, Carole Brewer, Jackie Cook, Rosemarie Davidson, Diana Eccles, Ros Eeles, Steve Ellis, EMBRACE, Debra Frost, Shirley Hodgson, Louise Izatt, Fiona Lalloo, Kai ren Ong, Andrew K. Godwin, Norbert Arnold, Bernd Dworniczak, Christoph Engel, Andrea Gehrig, Eric Hahnen, Jan Hauke, Karin Kast, Alfons Meindl, Dieter Niederacher, Raymonda Varon-Mateeva, Shan Wang-Gohrke, Barbara Wappenschmidt, Laure Barjhoux, Marie Agnès Collonge-Rame, Camille Elan, Study Collaborators GEMO Study Collaborators, Lisa Golmard, Emmanuelle Barouk-Simonet, Fabienne Lesueur, Sylvie Mazoyer, Joanna Sokolowska, Dominique StoppaLyonnet, Claudine Isaacs, Kathleen B.M. Claes, Bruce Poppe, Miguel de la Hoya, Vanesa Garcia-Barberan, Kristiina Aittomäki, Heli Nevanlinna, Margreet G.E.M. Ausems, J. L. de Lange, Encarna B. Gomez Garcia, HEBON, Frans B.L. Hogervorst, Carolien M. Kets, Hanne E.J. Meijers-Heijboer, Jan C. Oosterwijk, Matti A. Rookus, Christi J. van Asperen, Ans M.W. van den Ouweland, Helena C. van Doorn, Theo A.M. van Os, Ava Kwong, Edith Olah, Orland Diez, Joan Brunet, Conxi Lazaro, Alex Teulé, Jacek Gronwald, Anna Jakubowska, Katarzyna Kaczmarek, Jan Lubinski, Grzegorz Sukiennicki, Rosa B. Barkardottir, Jocelyne Chiquette, Simona Agata, Marco Montagna, Manuel R. Teixeira, KCon Fab Investigators, Sue Kyung Park, Curtis Olswold, Marc Tischkowitz, Lenka Foretova, Pragna Gaddam, Joseph Vijai, Georg Pfeiler, Christine Rappaport-Fuerhauser, Christian F. Singer, Muy Kheng M. Tea, Mark H. Greene, Jennifer T. Loud, Gad Rennert, Evgeny N. Imyanitov, Peter J. Hulick, John L. Hays, Marion Piedmonte, Gustavo C. Rodriguez, Julie Martyn, Gord Glendon, Anna Marie Mulligan, Irene L. Andrulis, Amanda Ewart Toland, Uffe Birk Jensen, Torben A. Kruse, Inge Sokilde Pedersen, Mads Thomassen, Maria A. Caligo, Soo Hwang Teo, Raanan Berger, Eitan Friedman, Yael Laitman, Brita Arver, Ake Borg, Hans Ehrencrona, Johanna Rantala, Olufunmilayo I. Olopade, Patricia A. Ganz, Robert L. Nussbaum, Angela R. Bradbury, Katherine L. Nathanson, Banu K. Arun, Paul James, Beth Y. Karlan, Jenny Lester

^*Corresponding author for this work

Clinical Departments

Research output: Contribution to journal › Article › peer-review

229 Scopus citations

Abstract

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10^-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10^-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Original language	English
Journal	Journal of the National Cancer Institute
Volume	109
Issue number	7
DOIs	https://doi.org/10.1093/jnci/djw302
State	Published - 1 Jul 2017

Funding

Funders	Funder number
European Commission
National Cancer Institute	R01CA176785, P30CA008748, P50CA116201, U01CA116167, U10CA180868, UG1CA189867
Not added	184.021.007
Seventh Framework Programme	223175

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/jnci/djw302

Cite this

Kuchenbaecker, K. B., McGuffog, L., Barrowdale, D., Lee, A., Soucy, P., Dennis, J., Domchek, S. M., Robson, M., Spurdle, A. B., Ramus, S. J., Mavaddat, N., Terry, M. B., Neuhausen, S. L., Schmutzler, R. K., Simard, J., Pharoah, P. D. P., Offit, K., Couch, F. J., Chenevix-Trench, G., ... Lester, J. (2017). Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute, 109(7). https://doi.org/10.1093/jnci/djw302

@article{9ec927c30193426ab308d365ec4281c9,

title = "Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers",

abstract = "Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.",

author = "Kuchenbaecker, {Karoline B.} and Lesley McGuffog and Daniel Barrowdale and Andrew Lee and Penny Soucy and Joe Dennis and Domchek, {Susan M.} and Mark Robson and Spurdle, {Amanda B.} and Ramus, {Susan J.} and Nasim Mavaddat and Terry, {Mary Beth} and Neuhausen, {Susan L.} and Schmutzler, {Rita Katharina} and Jacques Simard and Pharoah, {Paul D.P.} and Kenneth Offit and Couch, {Fergus J.} and Georgia Chenevix-Trench and Easton, {Douglas F.} and Antoniou, {Antonis C.} and Sue Healey and Michael Lush and Ute Hamann and Melissa Southey and John, {Esther M.} and Chung, {Wendy K.} and Daly, {Mary B.} and Buys, {Saundra S.} and Goldgar, {David E.} and Dorfling, {Cecilia M.} and {van Rensburg}, {Elizabeth J.} and Ding, {Yuan Chun} and Bent Ejlertsen and Gerdes, {Anne Marie} and Hansen, {Thomas V.O.} and Susan Slager and Emily Hallberg and Javier Benitez and Ana Osorio and Nancy Cohen and William Lawler and Weitzel, {Jeffrey N.} and Paolo Peterlongo and Valeria Pensotti and Riccardo Dolcetti and Monica Barile and Bernardo Bonanni and Jacopo Azzollini and Siranoush Manoukian and Bernard Peissel and Paolo Radice and Antonella Savarese and Laura Papi and Giuseppe Giannini and Florentia Fostira and Irene Konstantopoulou and Julian Adlard and Carole Brewer and Jackie Cook and Rosemarie Davidson and Diana Eccles and Ros Eeles and Steve Ellis and EMBRACE and Debra Frost and Shirley Hodgson and Louise Izatt and Fiona Lalloo and Ong, {Kai ren} and Godwin, {Andrew K.} and Norbert Arnold and Bernd Dworniczak and Christoph Engel and Andrea Gehrig and Eric Hahnen and Jan Hauke and Karin Kast and Alfons Meindl and Dieter Niederacher and Raymonda Varon-Mateeva and Shan Wang-Gohrke and Barbara Wappenschmidt and Laure Barjhoux and Collonge-Rame, {Marie Agn{\`e}s} and Camille Elan and {GEMO Study Collaborators}, {Study Collaborators} and Lisa Golmard and Emmanuelle Barouk-Simonet and Fabienne Lesueur and Sylvie Mazoyer and Joanna Sokolowska and Dominique StoppaLyonnet and Claudine Isaacs and Claes, {Kathleen B.M.} and Bruce Poppe and {de la Hoya}, Miguel and Vanesa Garcia-Barberan and Kristiina Aittom{\"a}ki and Heli Nevanlinna and Ausems, {Margreet G.E.M.} and {de Lange}, {J. L.} and {Gomez Garcia}, {Encarna B.} and HEBON and Hogervorst, {Frans B.L.} and Kets, {Carolien M.} and Meijers-Heijboer, {Hanne E.J.} and Oosterwijk, {Jan C.} and Rookus, {Matti A.} and {van Asperen}, {Christi J.} and {van den Ouweland}, {Ans M.W.} and {van Doorn}, {Helena C.} and {van Os}, {Theo A.M.} and Ava Kwong and Edith Olah and Orland Diez and Joan Brunet and Conxi Lazaro and Alex Teul{\'e} and Jacek Gronwald and Anna Jakubowska and Katarzyna Kaczmarek and Jan Lubinski and Grzegorz Sukiennicki and Barkardottir, {Rosa B.} and Jocelyne Chiquette and Simona Agata and Marco Montagna and Teixeira, {Manuel R.} and Investigators, {KCon Fab} and Park, {Sue Kyung} and Curtis Olswold and Marc Tischkowitz and Lenka Foretova and Pragna Gaddam and Joseph Vijai and Georg Pfeiler and Christine Rappaport-Fuerhauser and Singer, {Christian F.} and Tea, {Muy Kheng M.} and Greene, {Mark H.} and Loud, {Jennifer T.} and Gad Rennert and Imyanitov, {Evgeny N.} and Hulick, {Peter J.} and Hays, {John L.} and Marion Piedmonte and Rodriguez, {Gustavo C.} and Julie Martyn and Gord Glendon and Mulligan, {Anna Marie} and Andrulis, {Irene L.} and Toland, {Amanda Ewart} and Jensen, {Uffe Birk} and Kruse, {Torben A.} and Pedersen, {Inge Sokilde} and Mads Thomassen and Caligo, {Maria A.} and Teo, {Soo Hwang} and Raanan Berger and Eitan Friedman and Yael Laitman and Brita Arver and Ake Borg and Hans Ehrencrona and Johanna Rantala and Olopade, {Olufunmilayo I.} and Ganz, {Patricia A.} and Nussbaum, {Robert L.} and Bradbury, {Angela R.} and Nathanson, {Katherine L.} and Arun, {Banu K.} and Paul James and Karlan, {Beth Y.} and Jenny Lester",

note = "Publisher Copyright: {\textcopyright} The Author 2017.",

year = "2017",

month = jul,

day = "1",

doi = "10.1093/jnci/djw302",

language = "אנגלית",

volume = "109",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "7",

}

Kuchenbaecker, KB, McGuffog, L, Barrowdale, D, Lee, A, Soucy, P, Dennis, J, Domchek, SM, Robson, M, Spurdle, AB, Ramus, SJ, Mavaddat, N, Terry, MB, Neuhausen, SL, Schmutzler, RK, Simard, J, Pharoah, PDP, Offit, K, Couch, FJ, Chenevix-Trench, G, Easton, DF, Antoniou, AC, Healey, S, Lush, M, Hamann, U, Southey, M, John, EM, Chung, WK, Daly, MB, Buys, SS, Goldgar, DE, Dorfling, CM, van Rensburg, EJ, Ding, YC, Ejlertsen, B, Gerdes, AM, Hansen, TVO, Slager, S, Hallberg, E, Benitez, J, Osorio, A, Cohen, N, Lawler, W, Weitzel, JN, Peterlongo, P, Pensotti, V, Dolcetti, R, Barile, M, Bonanni, B, Azzollini, J, Manoukian, S, Peissel, B, Radice, P, Savarese, A, Papi, L, Giannini, G, Fostira, F, Konstantopoulou, I, Adlard, J, Brewer, C, Cook, J, Davidson, R, Eccles, D, Eeles, R, Ellis, S, EMBRACE, Frost, D, Hodgson, S, Izatt, L, Lalloo, F, Ong, KR, Godwin, AK, Arnold, N, Dworniczak, B, Engel, C, Gehrig, A, Hahnen, E, Hauke, J, Kast, K, Meindl, A, Niederacher, D, Varon-Mateeva, R, Wang-Gohrke, S, Wappenschmidt, B, Barjhoux, L, Collonge-Rame, MA, Elan, C, GEMO Study Collaborators, SC, Golmard, L, Barouk-Simonet, E, Lesueur, F, Mazoyer, S, Sokolowska, J, StoppaLyonnet, D, Isaacs, C, Claes, KBM, Poppe, B, de la Hoya, M, Garcia-Barberan, V, Aittomäki, K, Nevanlinna, H, Ausems, MGEM, de Lange, JL, Gomez Garcia, EB, HEBON, Hogervorst, FBL, Kets, CM, Meijers-Heijboer, HEJ, Oosterwijk, JC, Rookus, MA, van Asperen, CJ, van den Ouweland, AMW, van Doorn, HC, van Os, TAM, Kwong, A, Olah, E, Diez, O, Brunet, J, Lazaro, C, Teulé, A, Gronwald, J, Jakubowska, A, Kaczmarek, K, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Chiquette, J, Agata, S, Montagna, M, Teixeira, MR, Investigators, KCF, Park, SK, Olswold, C, Tischkowitz, M, Foretova, L, Gaddam, P, Vijai, J, Pfeiler, G, Rappaport-Fuerhauser, C, Singer, CF, Tea, MKM, Greene, MH, Loud, JT, Rennert, G, Imyanitov, EN, Hulick, PJ, Hays, JL, Piedmonte, M, Rodriguez, GC, Martyn, J, Glendon, G, Mulligan, AM, Andrulis, IL, Toland, AE, Jensen, UB, Kruse, TA, Pedersen, IS, Thomassen, M, Caligo, MA, Teo, SH, Berger, R , Friedman, E, Laitman, Y, Arver, B, Borg, A, Ehrencrona, H, Rantala, J, Olopade, OI, Ganz, PA, Nussbaum, RL, Bradbury, AR, Nathanson, KL, Arun, BK, James, P, Karlan, BY & Lester, J 2017, 'Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers', Journal of the National Cancer Institute, vol. 109, no. 7. https://doi.org/10.1093/jnci/djw302

TY - JOUR

T1 - Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

AU - Kuchenbaecker, Karoline B.

AU - McGuffog, Lesley

AU - Barrowdale, Daniel

AU - Lee, Andrew

AU - Soucy, Penny

AU - Dennis, Joe

AU - Domchek, Susan M.

AU - Robson, Mark

AU - Spurdle, Amanda B.

AU - Ramus, Susan J.

AU - Mavaddat, Nasim

AU - Terry, Mary Beth

AU - Neuhausen, Susan L.

AU - Schmutzler, Rita Katharina

AU - Simard, Jacques

AU - Pharoah, Paul D.P.

AU - Offit, Kenneth

AU - Couch, Fergus J.

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

AU - Antoniou, Antonis C.

AU - Healey, Sue

AU - Lush, Michael

AU - Hamann, Ute

AU - Southey, Melissa

AU - John, Esther M.

AU - Chung, Wendy K.

AU - Daly, Mary B.

AU - Buys, Saundra S.

AU - Goldgar, David E.

AU - Dorfling, Cecilia M.

AU - van Rensburg, Elizabeth J.

AU - Ding, Yuan Chun

AU - Ejlertsen, Bent

AU - Gerdes, Anne Marie

AU - Hansen, Thomas V.O.

AU - Slager, Susan

AU - Hallberg, Emily

AU - Benitez, Javier

AU - Osorio, Ana

AU - Cohen, Nancy

AU - Lawler, William

AU - Weitzel, Jeffrey N.

AU - Peterlongo, Paolo

AU - Pensotti, Valeria

AU - Dolcetti, Riccardo

AU - Barile, Monica

AU - Bonanni, Bernardo

AU - Azzollini, Jacopo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Radice, Paolo

AU - Savarese, Antonella

AU - Papi, Laura

AU - Giannini, Giuseppe

AU - Fostira, Florentia

AU - Konstantopoulou, Irene

AU - Adlard, Julian

AU - Brewer, Carole

AU - Cook, Jackie

AU - Davidson, Rosemarie

AU - Eccles, Diana

AU - Eeles, Ros

AU - Ellis, Steve

AU - EMBRACE,

AU - Frost, Debra

AU - Hodgson, Shirley

AU - Izatt, Louise

AU - Lalloo, Fiona

AU - Ong, Kai ren

AU - Godwin, Andrew K.

AU - Arnold, Norbert

AU - Dworniczak, Bernd

AU - Engel, Christoph

AU - Gehrig, Andrea

AU - Hahnen, Eric

AU - Hauke, Jan

AU - Kast, Karin

AU - Meindl, Alfons

AU - Niederacher, Dieter

AU - Varon-Mateeva, Raymonda

AU - Wang-Gohrke, Shan

AU - Wappenschmidt, Barbara

AU - Barjhoux, Laure

AU - Collonge-Rame, Marie Agnès

AU - Elan, Camille

AU - GEMO Study Collaborators, Study Collaborators

AU - Golmard, Lisa

AU - Barouk-Simonet, Emmanuelle

AU - Lesueur, Fabienne

AU - Mazoyer, Sylvie

AU - Sokolowska, Joanna

AU - StoppaLyonnet, Dominique

AU - Isaacs, Claudine

AU - Claes, Kathleen B.M.

AU - Poppe, Bruce

AU - de la Hoya, Miguel

AU - Garcia-Barberan, Vanesa

AU - Aittomäki, Kristiina

AU - Nevanlinna, Heli

AU - Ausems, Margreet G.E.M.

AU - de Lange, J. L.

AU - Gomez Garcia, Encarna B.

AU - HEBON,

AU - Hogervorst, Frans B.L.

AU - Kets, Carolien M.

AU - Meijers-Heijboer, Hanne E.J.

AU - Oosterwijk, Jan C.

AU - Rookus, Matti A.

AU - van Asperen, Christi J.

AU - van den Ouweland, Ans M.W.

AU - van Doorn, Helena C.

AU - van Os, Theo A.M.

AU - Kwong, Ava

AU - Olah, Edith

AU - Diez, Orland

AU - Brunet, Joan

AU - Lazaro, Conxi

AU - Teulé, Alex

AU - Gronwald, Jacek

AU - Jakubowska, Anna

AU - Kaczmarek, Katarzyna

AU - Lubinski, Jan

AU - Sukiennicki, Grzegorz

AU - Barkardottir, Rosa B.

AU - Chiquette, Jocelyne

AU - Agata, Simona

AU - Montagna, Marco

AU - Teixeira, Manuel R.

AU - Investigators, KCon Fab

AU - Park, Sue Kyung

AU - Olswold, Curtis

AU - Tischkowitz, Marc

AU - Foretova, Lenka

AU - Gaddam, Pragna

AU - Vijai, Joseph

AU - Pfeiler, Georg

AU - Rappaport-Fuerhauser, Christine

AU - Singer, Christian F.

AU - Tea, Muy Kheng M.

AU - Greene, Mark H.

AU - Loud, Jennifer T.

AU - Rennert, Gad

AU - Imyanitov, Evgeny N.

AU - Hulick, Peter J.

AU - Hays, John L.

AU - Piedmonte, Marion

AU - Rodriguez, Gustavo C.

AU - Martyn, Julie

AU - Glendon, Gord

AU - Mulligan, Anna Marie

AU - Andrulis, Irene L.

AU - Toland, Amanda Ewart

AU - Jensen, Uffe Birk

AU - Kruse, Torben A.

AU - Pedersen, Inge Sokilde

AU - Thomassen, Mads

AU - Caligo, Maria A.

AU - Teo, Soo Hwang

AU - Berger, Raanan

AU - Friedman, Eitan

AU - Laitman, Yael

AU - Arver, Brita

AU - Borg, Ake

AU - Ehrencrona, Hans

AU - Rantala, Johanna

AU - Olopade, Olufunmilayo I.

AU - Ganz, Patricia A.

AU - Nussbaum, Robert L.

AU - Bradbury, Angela R.

AU - Nathanson, Katherine L.

AU - Arun, Banu K.

AU - James, Paul

AU - Karlan, Beth Y.

AU - Lester, Jenny

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

AB - Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

UR - http://www.scopus.com/inward/record.url?scp=85016213460&partnerID=8YFLogxK

U2 - 10.1093/jnci/djw302

DO - 10.1093/jnci/djw302

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C2 - 28376175

AN - SCOPUS:85016213460

SN - 0027-8874

VL - 109

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 7

ER -

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

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