Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Daniel R. Barnes; Matti A. Rookus; Lesley McGuffog; Goska Leslie; Thea M. Mooij; Joe Dennis; Nasim Mavaddat; Julian Adlard; Munaza Ahmed; Kristiina Aittomaki; Nadine Andrieu; Irene L. Andrulis; Norbert Arnold; Banu K. Arun; Jacopo Azzollini; Judith Balmana; Rosa B. Barkardottir; Daniel Barrowdale; Javier Benitez; Pascaline Berthet; Katarzyna Bialkowska; Amie M. Blanco; Marinus J. Blok; Bernardo Bonanni; Susanne E. Boonen; Ake Borg; Aniko Bozsik; Angela R. Bradbury; Paul Brennan; Carole Brewer; Joan Brunet; Saundra S. Buys; Trinidad Caldes; Maria A. Caligo; Ian Campbell; Lise Lotte Christensen; Wendy K. Chung; Kathleen B. M. Claes; Chrystelle Colas; Marie-Agnes Collonge-Rame; Jackie Cook; Mary B. Daly; Rosemarie Davidson; Miguel de la Hoya; Robin de Putter; Capucine Delnatte; Peter Devilee; Orland Diez; Yuan Chun Ding; Susan M. Domchek; GEMO Study Collaborators; EMBRACE Collaborators; KConFab Investigators; HEBON Investigators; Consortium of Investigators of Modifiers of BRCA and BRCA2

doi:10.1038/s41436-020-0862-x

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Daniel R. Barnes^*, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomaki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmana, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline BerthetKatarzyna Bialkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Ake Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B. M. Claes, Chrystelle Colas, Marie-Agnes Collonge-Rame, Jackie Cook, Mary B. Daly, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, Consortium of Investigators of Modifiers of BRCA and BRCA2

^*Corresponding author for this work

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

Abstract

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10 ⁻⁷²). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10 ⁻⁵⁰). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10 ⁻²²) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10 ⁻¹²) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Original language	English
Pages (from-to)	1653-1666
Number of pages	14
Journal	Genetics in Medicine
Volume	22
Issue number	10
DOIs	https://doi.org/10.1038/s41436-020-0862-x
Publication status	Published - Oct 2020

Keywords

BRCA1
2
breast cancer
ovarian cancer
PRS
genetics
MUTATION CARRIERS
SUSCEPTIBILITY
ASSOCIATION
PATHOLOGY
IDENTIFICATION
MODIFIERS
ALLELES
MODEL

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Barnes, D. R., Rookus, M. A., McGuffog, L., Leslie, G., Mooij, T. M., Dennis, J., Mavaddat, N., Adlard, J., Ahmed, M., Aittomaki, K., Andrieu, N., Andrulis, I. L., Arnold, N., Arun, B. K., Azzollini, J., Balmana, J., Barkardottir, R. B., Barrowdale, D., Benitez, J., ... Consortium of Investigators of Modifiers of BRCA and BRCA2 (2020). Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genetics in Medicine, 22(10), 1653-1666. https://doi.org/10.1038/s41436-020-0862-x

@article{7f62a81b743f44d0881a85ed49ce094e,

title = "Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants",

abstract = "Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10 −72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10 −50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10 −22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10 −12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.",

keywords = "BRCA1, 2, breast cancer, ovarian cancer, PRS, genetics, MUTATION CARRIERS, SUSCEPTIBILITY, ASSOCIATION, PATHOLOGY, IDENTIFICATION, MODIFIERS, ALLELES, MODEL",

author = "Barnes, {Daniel R.} and Rookus, {Matti A.} and Lesley McGuffog and Goska Leslie and Mooij, {Thea M.} and Joe Dennis and Nasim Mavaddat and Julian Adlard and Munaza Ahmed and Kristiina Aittomaki and Nadine Andrieu and Andrulis, {Irene L.} and Norbert Arnold and Arun, {Banu K.} and Jacopo Azzollini and Judith Balmana and Barkardottir, {Rosa B.} and Daniel Barrowdale and Javier Benitez and Pascaline Berthet and Katarzyna Bialkowska and Blanco, {Amie M.} and Blok, {Marinus J.} and Bernardo Bonanni and Boonen, {Susanne E.} and Ake Borg and Aniko Bozsik and Bradbury, {Angela R.} and Paul Brennan and Carole Brewer and Joan Brunet and Buys, {Saundra S.} and Trinidad Caldes and Caligo, {Maria A.} and Ian Campbell and Christensen, {Lise Lotte} and Chung, {Wendy K.} and Claes, {Kathleen B. M.} and Chrystelle Colas and Marie-Agnes Collonge-Rame and Jackie Cook and Daly, {Mary B.} and Rosemarie Davidson and {de la Hoya}, Miguel and {de Putter}, Robin and Capucine Delnatte and Peter Devilee and Orland Diez and Ding, {Yuan Chun} and Domchek, {Susan M.} and {GEMO Study Collaborators} and {EMBRACE Collaborators} and {KConFab Investigators} and {HEBON Investigators} and {Consortium of Investigators of Modifiers of BRCA and BRCA2}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = oct,

doi = "10.1038/s41436-020-0862-x",

language = "English",

volume = "22",

pages = "1653--1666",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "10",

}

Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators & Consortium of Investigators of Modifiers of BRCA and BRCA2 2020, 'Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants', Genetics in Medicine, vol. 22, no. 10, pp. 1653-1666. https://doi.org/10.1038/s41436-020-0862-x

TY - JOUR

T1 - Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

AU - Barnes, Daniel R.

AU - Rookus, Matti A.

AU - McGuffog, Lesley

AU - Leslie, Goska

AU - Mooij, Thea M.

AU - Dennis, Joe

AU - Mavaddat, Nasim

AU - Adlard, Julian

AU - Ahmed, Munaza

AU - Aittomaki, Kristiina

AU - Andrieu, Nadine

AU - Andrulis, Irene L.

AU - Arnold, Norbert

AU - Arun, Banu K.

AU - Azzollini, Jacopo

AU - Balmana, Judith

AU - Barkardottir, Rosa B.

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Berthet, Pascaline

AU - Bialkowska, Katarzyna

AU - Blanco, Amie M.

AU - Blok, Marinus J.

AU - Bonanni, Bernardo

AU - Boonen, Susanne E.

AU - Borg, Ake

AU - Bozsik, Aniko

AU - Bradbury, Angela R.

AU - Brennan, Paul

AU - Brewer, Carole

AU - Brunet, Joan

AU - Buys, Saundra S.

AU - Caldes, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Christensen, Lise Lotte

AU - Chung, Wendy K.

AU - Claes, Kathleen B. M.

AU - Colas, Chrystelle

AU - Collonge-Rame, Marie-Agnes

AU - Cook, Jackie

AU - Daly, Mary B.

AU - Davidson, Rosemarie

AU - de la Hoya, Miguel

AU - de Putter, Robin

AU - Delnatte, Capucine

AU - Devilee, Peter

AU - Diez, Orland

AU - Ding, Yuan Chun

AU - Domchek, Susan M.

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - KConFab Investigators

AU - HEBON Investigators

AU - Consortium of Investigators of Modifiers of BRCA and BRCA2

PY - 2020/10

Y1 - 2020/10

N2 - Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10 −72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10 −50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10 −22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10 −12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

AB - Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10 −72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10 −50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10 −22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10 −12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

KW - BRCA1

KW - 2

KW - breast cancer

KW - ovarian cancer

KW - PRS

KW - genetics

KW - MUTATION CARRIERS

KW - SUSCEPTIBILITY

KW - ASSOCIATION

KW - PATHOLOGY

KW - IDENTIFICATION

KW - MODIFIERS

KW - ALLELES

KW - MODEL

U2 - 10.1038/s41436-020-0862-x

DO - 10.1038/s41436-020-0862-x

M3 - Article

C2 - 32665703

SN - 1098-3600

VL - 22

SP - 1653

EP - 1666

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

ER -