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 Aittomäki; Nadine Andrieu; Irene L Andrulis; Norbert Arnold; Banu K Arun; Jacopo Azzollini; Judith Balmaña; Rosa B Barkardottir; Daniel Barrowdale; Javier Benitez; Pascaline Berthet; Katarzyna Białkowska; Amie M Blanco; Marinus J Blok; Bernardo Bonanni; Susanne E Boonen; Åke Borg; Aniko Bozsik; Angela R Bradbury; Paul Brennan; Carole Brewer; Joan Brunet; Saundra S Buys; Trinidad Caldés; Maria A Caligo; Ian Campbell; Lise Lotte Christensen; Wendy K Chung; Kathleen B M Claes; Chrystelle Colas; Marie-Agnès 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; Inge Sokilde Pedersen

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 Aittomäki, Nadine Andrieu, Irene L Andrulis, Norbert Arnold, Banu K Arun, Jacopo Azzollini, Judith Balmaña, Rosa B Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline BerthetKatarzyna Białkowska, Amie M Blanco, Marinus J Blok, Bernardo Bonanni, Susanne E Boonen, Åke Borg, Aniko Bozsik, Angela R Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K Chung, Kathleen B M Claes, Chrystelle Colas, Marie-Agnès 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, Inge Sokilde Pedersen

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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.

Originalsprog	Engelsk
Tidsskrift	Genetics in Medicine
Vol/bind	22
Udgave nummer	10
Sider (fra-til)	1653-1666
Antal sider	14
ISSN	1098-3600
DOI	https://doi.org/10.1038/s41436-020-0862-x
Status	Udgivet - okt. 2020

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10.1038/s41436-020-0862-xLicens: CC BY 4.0

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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., Aittomäki, K., Andrieu, N., Andrulis, I. L., Arnold, N., Arun, B. K., Azzollini, J., Balmaña, J., Barkardottir, R. B., Barrowdale, D., Benitez, J., ... Pedersen, I. S. (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

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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.",

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 Aittom{\"a}ki and Nadine Andrieu and Andrulis, {Irene L} and Norbert Arnold and Arun, {Banu K} and Jacopo Azzollini and Judith Balma{\~n}a and Barkardottir, {Rosa B} and Daniel Barrowdale and Javier Benitez and Pascaline Berthet and Katarzyna Bia{\l}kowska and Blanco, {Amie M} and Blok, {Marinus J} and Bernardo Bonanni and Boonen, {Susanne E} and {\AA}ke Borg and Aniko Bozsik and Bradbury, {Angela R} and Paul Brennan and Carole Brewer and Joan Brunet and Buys, {Saundra S} and Trinidad Cald{\'e}s 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-Agn{\`e}s 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 Pedersen, {Inge Sokilde}",

note = "See the complete list of authors in the article.",

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",

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Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomäki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmaña, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Białkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, Å, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldés, 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 & Pedersen, IS 2020, 'Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants', Genetics in Medicine, bind 22, nr. 10, s. 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 - Aittomäki, Kristiina

AU - Andrieu, Nadine

AU - Andrulis, Irene L

AU - Arnold, Norbert

AU - Arun, Banu K

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barkardottir, Rosa B

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Berthet, Pascaline

AU - Białkowska, Katarzyna

AU - Blanco, Amie M

AU - Blok, Marinus J

AU - Bonanni, Bernardo

AU - Boonen, Susanne E

AU - Borg, Åke

AU - Bozsik, Aniko

AU - Bradbury, Angela R

AU - Brennan, Paul

AU - Brewer, Carole

AU - Brunet, Joan

AU - Buys, Saundra S

AU - Caldés, 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-Agnès

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 - Pedersen, Inge Sokilde

N1 - See the complete list of authors in the article.

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.

U2 - 10.1038/s41436-020-0862-x

DO - 10.1038/s41436-020-0862-x

M3 - Journal article

C2 - 32665703

SN - 1098-3600

VL - 22

SP - 1653

EP - 1666

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

ER -

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

Abstract

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