Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Daniel R Barnes; Valentina Silvestri; Goska Leslie; Lesley McGuffog; Joe Dennis; Xin Yang; Julian Adlard; Bjarni A Agnarsson; Munaza Ahmed; Kristiina Aittomäki; Irene L Andrulis; Adalgeir Arason; Norbert Arnold; Bernd Auber; Jacopo Azzollini; Judith Balmaña; Rosa B Barkardottir; Daniel Barrowdale; Julian Barwell; Muriel Belotti; Javier Benitez; Pascaline Berthet; Susanne E Boonen; Åke Borg; Aniko Bozsik; Angela F Brady; Paul Brennan; Carole Brewer; Joan Brunet; Agostino Bucalo; Saundra S Buys; Trinidad Caldés; Maria A Caligo; Ian Campbell; Hayley Cassingham; Lise Lotte Christensen; Giulia Cini; Kathleen B M Claes; Jackie Cook; Anna Coppa; Laura Cortesi; Giuseppe Damante; Esther Darder; Rosemarie Davidson; Miguel de la Hoya; Thomas V O Hansen; Torben A Kruse; Inge Sokilde Pedersen; Karina Rønlund; Mads Thomassen; GEMO Study Collaborators; Lone Krøldrup Kristensen; Uffe Birk Jensen; Charlotte K. Lautrup; Annabeth  Høgh Petersen

doi:10.1093/jnci/djab147

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Daniel R Barnes^*, Valentina Silvestri, Goska Leslie, Lesley McGuffog, Joe Dennis, Xin Yang, Julian Adlard, Bjarni A Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Bernd Auber, Jacopo Azzollini, Judith Balmaña, Rosa B Barkardottir, Daniel Barrowdale, Julian Barwell, Muriel BelottiJavier Benitez, Pascaline Berthet, Susanne E Boonen, Åke Borg, Aniko Bozsik, Angela F Brady, Paul Brennan, Carole Brewer, Joan Brunet, Agostino Bucalo, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Ian Campbell, Hayley Cassingham, Lise Lotte Christensen, Giulia Cini, Kathleen B M Claes, Jackie Cook, Anna Coppa, Laura Cortesi, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de la Hoya, Thomas V O Hansen, Torben A Kruse, Inge Sokilde Pedersen, Karina Rønlund, Mads Thomassen, GEMO Study Collaborators, Lone Krøldrup Kristensen, Uffe Birk Jensen, Charlotte K. Lautrup, Annabeth Høgh Petersen

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.

RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Original language	English
Article number	djab147
Journal	National Cancer Institute. Journal (Online)
Volume	114
Issue number	1
Pages (from-to)	109-122
ISSN	1460-2105
DOIs	https://doi.org/10.1093/jnci/djab147
Publication status	Published - Jan 2022

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10.1093/jnci/djab147Licence: CC BY

Open access versionFinal published version, 6.24 MBLicence: CC BY

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Barnes, D. R., Silvestri, V., Leslie, G., McGuffog, L., Dennis, J., Yang, X., Adlard, J., Agnarsson, B. A., Ahmed, M., Aittomäki, K., Andrulis, I. L., Arason, A., Arnold, N., Auber, B., Azzollini, J., Balmaña, J., Barkardottir, R. B., Barrowdale, D., Barwell, J., ... Høgh Petersen, A. (2022). Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores. National Cancer Institute. Journal (Online), 114(1), 109-122. Article djab147. https://doi.org/10.1093/jnci/djab147

@article{752d7c4be9b442f19e526c6bdc3f2110,

title = "Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores",

abstract = "BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.",

author = "Barnes, {Daniel R} and Valentina Silvestri and Goska Leslie and Lesley McGuffog and Joe Dennis and Xin Yang and Julian Adlard and Agnarsson, {Bjarni A} and Munaza Ahmed and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Adalgeir Arason and Norbert Arnold and Bernd Auber and Jacopo Azzollini and Judith Balma{\~n}a and Barkardottir, {Rosa B} and Daniel Barrowdale and Julian Barwell and Muriel Belotti and Javier Benitez and Pascaline Berthet and Boonen, {Susanne E} and {\AA}ke Borg and Aniko Bozsik and Brady, {Angela F} and Paul Brennan and Carole Brewer and Joan Brunet and Agostino Bucalo and Buys, {Saundra S} and Trinidad Cald{\'e}s and Caligo, {Maria A} and Ian Campbell and Hayley Cassingham and Christensen, {Lise Lotte} and Giulia Cini and Claes, {Kathleen B M} and Jackie Cook and Anna Coppa and Laura Cortesi and Giuseppe Damante and Esther Darder and Rosemarie Davidson and {de la Hoya}, Miguel and Hansen, {Thomas V O} and Kruse, {Torben A} and Pedersen, {Inge Sokilde} and Karina R{\o}nlund and Mads Thomassen and {GEMO Study Collaborators} and Kristensen, {Lone Kr{\o}ldrup} and Jensen, {Uffe Birk} and Lautrup, {Charlotte K.} and {H{\o}gh Petersen}, Annabeth",

note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press.",

year = "2022",

month = jan,

doi = "10.1093/jnci/djab147",

language = "English",

volume = "114",

pages = "109--122",

journal = "National Cancer Institute. Journal (Online)",

issn = "1460-2105",

publisher = "Oxford University Press",

number = "1",

}

Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomäki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmaña, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, Å, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldés, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Hansen, TVO, Kruse, TA, Pedersen, IS, Rønlund, K, Thomassen, M, GEMO Study Collaborators, Kristensen, LK, Jensen, UB, Lautrup, CK & Høgh Petersen, A 2022, 'Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores', National Cancer Institute. Journal (Online), vol. 114, no. 1, djab147, pp. 109-122. https://doi.org/10.1093/jnci/djab147

TY - JOUR

T1 - Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

AU - Barnes, Daniel R

AU - Silvestri, Valentina

AU - Leslie, Goska

AU - McGuffog, Lesley

AU - Dennis, Joe

AU - Yang, Xin

AU - Adlard, Julian

AU - Agnarsson, Bjarni A

AU - Ahmed, Munaza

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L

AU - Arason, Adalgeir

AU - Arnold, Norbert

AU - Auber, Bernd

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barkardottir, Rosa B

AU - Barrowdale, Daniel

AU - Barwell, Julian

AU - Belotti, Muriel

AU - Benitez, Javier

AU - Berthet, Pascaline

AU - Boonen, Susanne E

AU - Borg, Åke

AU - Bozsik, Aniko

AU - Brady, Angela F

AU - Brennan, Paul

AU - Brewer, Carole

AU - Brunet, Joan

AU - Bucalo, Agostino

AU - Buys, Saundra S

AU - Caldés, Trinidad

AU - Caligo, Maria A

AU - Campbell, Ian

AU - Cassingham, Hayley

AU - Christensen, Lise Lotte

AU - Cini, Giulia

AU - Claes, Kathleen B M

AU - Cook, Jackie

AU - Coppa, Anna

AU - Cortesi, Laura

AU - Damante, Giuseppe

AU - Darder, Esther

AU - Davidson, Rosemarie

AU - de la Hoya, Miguel

AU - Hansen, Thomas V O

AU - Kruse, Torben A

AU - Pedersen, Inge Sokilde

AU - Rønlund, Karina

AU - Thomassen, Mads

AU - GEMO Study Collaborators

AU - Kristensen, Lone Krøldrup

AU - Jensen, Uffe Birk

AU - Lautrup, Charlotte K.

AU - Høgh Petersen, Annabeth

PY - 2022/1

Y1 - 2022/1

N2 - BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

AB - BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

U2 - 10.1093/jnci/djab147

DO - 10.1093/jnci/djab147

M3 - Journal article

C2 - 34320204

SN - 1460-2105

VL - 114

SP - 109

EP - 122

JO - National Cancer Institute. Journal (Online)

JF - National Cancer Institute. Journal (Online)

IS - 1

M1 - djab147

ER -

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Abstract

Bibliographical note

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