The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

GEMO Study Collaborators; Inge M M Lakeman; Alexandra J van den Broek; Juliën A M Vos; Daniel R Barnes; Julian Adlard; Irene L Andrulis; Adalgeir Arason; Norbert Arnold; Banu K Arun; Judith Balmaña; Daniel Barrowdale; Javier Benitez; Ake Borg; Trinidad Caldés; Maria A Caligo; Wendy K Chung; Kathleen B M Claes; J Margriet Collée; Fergus J Couch; Mary B Daly; Joe Dennis; Mallika Dhawan; Susan M Domchek; Ros Eeles; Christoph Engel; D Gareth Evans; Lidia Feliubadaló; Lenka Foretova; Eitan Friedman; Debra Frost; Patricia A Ganz; Judy Garber; Simon A Gayther; Anne-Marie Gerdes; Andrew K Godwin; David E Goldgar; Eric Hahnen; Christopher R Hake; Ute Hamann; Frans B L Hogervorst; Maartje J Hooning; John L Hopper; Peter J Hulick; Evgeny N Imyanitov; Claudine Isaacs; Louise Izatt; Anna Jakubowska; Paul A James; Ramunas Janavicius; Uffe Birk Jensen

doi:10.1038/s41436-021-01198-7

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

GEMO Study Collaborators, Inge M M Lakeman, Alexandra J van den Broek, Juliën A M Vos, Daniel R Barnes, Julian Adlard, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Banu K Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A Caligo, Wendy K Chung, Kathleen B M Claes, J Margriet Collée, Fergus J CouchMary B Daly, Joe Dennis, Mallika Dhawan, Susan M Domchek, Ros Eeles, Christoph Engel, D Gareth Evans, Lidia Feliubadaló, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A Ganz, Judy Garber, Simon A Gayther, Anne-Marie Gerdes, Andrew K Godwin, David E Goldgar, Eric Hahnen, Christopher R Hake, Ute Hamann, Frans B L Hogervorst, Maartje J Hooning, John L Hopper, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Paul A James, Ramunas Janavicius, Uffe Birk Jensen

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

18 Scopus citations

Abstract

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.

RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

Original language	English
Pages (from-to)	1726-1737
Number of pages	12
Journal	Genetics in Medicine
Volume	23
Issue number	9
DOIs	https://doi.org/10.1038/s41436-021-01198-7
State	Published - Sep 2021

Keywords

Adult
BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/diagnosis
Female
Genetic Predisposition to Disease
Heterozygote
Humans
Mutation
Retrospective Studies
Risk Factors

UN SDGs

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

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10.1038/s41436-021-01198-7

Cite this

GEMO Study Collaborators, Lakeman, I. M. M., van den Broek, A. J., Vos, J. A. M., Barnes, D. R., Adlard, J., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Balmaña, J., Barrowdale, D., Benitez, J., Borg, A., Caldés, T., Caligo, M. A., Chung, W. K., Claes, K. B. M., Collée, J. M., ... Jensen, U. B. (2021). The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant. Genetics in Medicine, 23(9), 1726-1737. https://doi.org/10.1038/s41436-021-01198-7

@article{3b275a92621742689d5ab78b7cf4fd6b,

title = "The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant",

abstract = "PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.",

keywords = "Adult, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/diagnosis, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Retrospective Studies, Risk Factors",

author = "{GEMO Study Collaborators} and Lakeman, {Inge M M} and {van den Broek}, {Alexandra J} and Vos, {Juli{\"e}n A M} and Barnes, {Daniel R} and Julian Adlard and Andrulis, {Irene L} and Adalgeir Arason and Norbert Arnold and Arun, {Banu K} and Judith Balma{\~n}a and Daniel Barrowdale and Javier Benitez and Ake Borg and Trinidad Cald{\'e}s and Caligo, {Maria A} and Chung, {Wendy K} and Claes, {Kathleen B M} and Coll{\'e}e, {J Margriet} and Couch, {Fergus J} and Daly, {Mary B} and Joe Dennis and Mallika Dhawan and Domchek, {Susan M} and Ros Eeles and Christoph Engel and Evans, {D Gareth} and Lidia Feliubadal{\'o} and Lenka Foretova and Eitan Friedman and Debra Frost and Ganz, {Patricia A} and Judy Garber and Gayther, {Simon A} and Anne-Marie Gerdes and Godwin, {Andrew K} and Goldgar, {David E} and Eric Hahnen and Hake, {Christopher R} and Ute Hamann and Hogervorst, {Frans B L} and Hooning, {Maartje J} and Hopper, {John L} and Hulick, {Peter J} and Imyanitov, {Evgeny N} and Claudine Isaacs and Louise Izatt and Anna Jakubowska and James, {Paul A} and Ramunas Janavicius and Jensen, {Uffe Birk}",

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

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doi = "10.1038/s41436-021-01198-7",

language = "English",

volume = "23",

pages = "1726--1737",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

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GEMO Study Collaborators, Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmaña, J, Barrowdale, D, Benitez, J, Borg, A, Caldés, T, Caligo, MA, Chung, WK, Claes, KBM, Collée, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadaló, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R & Jensen, UB 2021, 'The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant', Genetics in Medicine, vol. 23, no. 9, pp. 1726-1737. https://doi.org/10.1038/s41436-021-01198-7

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant. / GEMO Study Collaborators; Lakeman, Inge M M; van den Broek, Alexandra J et al.
In: Genetics in Medicine, Vol. 23, No. 9, 09.2021, p. 1726-1737.

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

TY - JOUR

T1 - The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

AU - GEMO Study Collaborators

AU - Lakeman, Inge M M

AU - van den Broek, Alexandra J

AU - Vos, Juliën A M

AU - Barnes, Daniel R

AU - Adlard, Julian

AU - Andrulis, Irene L

AU - Arason, Adalgeir

AU - Arnold, Norbert

AU - Arun, Banu K

AU - Balmaña, Judith

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Borg, Ake

AU - Caldés, Trinidad

AU - Caligo, Maria A

AU - Chung, Wendy K

AU - Claes, Kathleen B M

AU - Collée, J Margriet

AU - Couch, Fergus J

AU - Daly, Mary B

AU - Dennis, Joe

AU - Dhawan, Mallika

AU - Domchek, Susan M

AU - Eeles, Ros

AU - Engel, Christoph

AU - Evans, D Gareth

AU - Feliubadaló, Lidia

AU - Foretova, Lenka

AU - Friedman, Eitan

AU - Frost, Debra

AU - Ganz, Patricia A

AU - Garber, Judy

AU - Gayther, Simon A

AU - Gerdes, Anne-Marie

AU - Godwin, Andrew K

AU - Goldgar, David E

AU - Hahnen, Eric

AU - Hake, Christopher R

AU - Hamann, Ute

AU - Hogervorst, Frans B L

AU - Hooning, Maartje J

AU - Hopper, John L

AU - Hulick, Peter J

AU - Imyanitov, Evgeny N

AU - Isaacs, Claudine

AU - Izatt, Louise

AU - Jakubowska, Anna

AU - James, Paul A

AU - Janavicius, Ramunas

AU - Jensen, Uffe Birk

PY - 2021/9

Y1 - 2021/9

N2 - PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

AB - PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

KW - Adult

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/diagnosis

KW - Female

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Mutation

KW - Retrospective Studies

KW - Risk Factors

UR - http://www.scopus.com/inward/record.url?scp=85115935642&partnerID=8YFLogxK

U2 - 10.1038/s41436-021-01198-7

DO - 10.1038/s41436-021-01198-7

M3 - Article

C2 - 34113011

SN - 1098-3600

VL - 23

SP - 1726

EP - 1737

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 9

ER -

GEMO Study Collaborators, Lakeman IMM, van den Broek AJ, Vos JAM, Barnes DR, Adlard J et al. The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant. Genetics in Medicine. 2021 Sep;23(9):1726-1737. doi: 10.1038/s41436-021-01198-7

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Abstract

Keywords

UN SDGs

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