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; Et al.; Encarna B. Gomez Garcia; Marinus Blok

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, Et al., Encarna B. Gomez Garcia, Marinus Blok

^*Corresponding author for this work

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

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
Article number	djw302
Journal	Journal of the National Cancer Institute
Volume	109
Issue number	7
DOIs	https://doi.org/10.1093/jnci/djw302
Publication status	Published - 1 Jul 2017

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10.1093/jnci/djw302Licence: CC BY

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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., ... Blok, M. (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), Article djw302. https://doi.org/10.1093/jnci/djw302

@article{4d8e3465cc9b455299291e202080c604,

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 {Et al.} and {Gomez Garcia}, {Encarna B.} and Marinus Blok",

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

year = "2017",

month = jul,

day = "1",

doi = "10.1093/jnci/djw302",

language = "English",

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, Et al., Gomez Garcia, EB & Blok, M 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, djw302. 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 - Et al.

AU - Gomez Garcia, Encarna B.

AU - Blok, Marinus

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.

U2 - 10.1093/jnci/djw302

DO - 10.1093/jnci/djw302

M3 - Article

SN - 0027-8874

VL - 109

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 7

M1 - djw302

ER -

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

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