Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases

Inge M M Lakeman; Mar D M Rodríguez-Girondo; Andrew Lee; Nandi Celosse; Merel E Braspenning; Klaartje van Engelen; Irma van de Beek; Annemiek H van der Hout; Encarna B Gómez García; Arjen R Mensenkamp; Margreet G E M Ausems; Maartje J Hooning; Muriel A Adank; Antoinette Hollestelle; Marjanka K Schmidt; Christi J van Asperen; Peter Devilee

doi:10.1136/jmg-2022-108502

Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases

Inge M M Lakeman, Mar D M Rodríguez-Girondo, Andrew Lee, Nandi Celosse, Merel E Braspenning, Klaartje van Engelen, Irma van de Beek, Annemiek H van der Hout, Encarna B Gómez García, Arjen R Mensenkamp, Margreet G E M Ausems, Maartje J Hooning, Muriel A Adank, Antoinette Hollestelle, Marjanka K Schmidt, Christi J van Asperen, Peter Devilee^*

^*Corresponding author for this work

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

Abstract

BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families.

METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known.

RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM.

CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

Original language	English
Number of pages	10
Journal	Journal of Medical Genetics
DOIs	https://doi.org/10.1136/jmg-2022-108502
Publication status	E-pub ahead of print - 22 Sept 2022

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Lakeman, I. M. M., Rodríguez-Girondo, M. D. M., Lee, A., Celosse, N., Braspenning, M. E., van Engelen, K., van de Beek, I., van der Hout, A. H., Gómez García, E. B., Mensenkamp, A. R., Ausems, M. G. E. M., Hooning, M. J., Adank, M. A., Hollestelle, A., Schmidt, M. K., van Asperen, C. J., & Devilee, P. (2022). Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases. Journal of Medical Genetics. https://doi.org/10.1136/jmg-2022-108502

@article{dd308c3e6fb140d5b68a4b87400c6517,

title = "Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases",

abstract = "BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families.METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known.RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM.CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.",

author = "Lakeman, {Inge M M} and Rodr{\'i}guez-Girondo, {Mar D M} and Andrew Lee and Nandi Celosse and Braspenning, {Merel E} and {van Engelen}, Klaartje and {van de Beek}, Irma and {van der Hout}, {Annemiek H} and {G{\'o}mez Garc{\'i}a}, {Encarna B} and Mensenkamp, {Arjen R} and Ausems, {Margreet G E M} and Hooning, {Maartje J} and Adank, {Muriel A} and Antoinette Hollestelle and Schmidt, {Marjanka K} and {van Asperen}, {Christi J} and Peter Devilee",

note = "{\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = sep,

day = "22",

doi = "10.1136/jmg-2022-108502",

language = "English",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

}

Lakeman, IMM, Rodríguez-Girondo, MDM, Lee, A, Celosse, N, Braspenning, ME, van Engelen, K, van de Beek, I, van der Hout, AH, Gómez García, EB, Mensenkamp, AR, Ausems, MGEM, Hooning, MJ, Adank, MA, Hollestelle, A, Schmidt, MK, van Asperen, CJ & Devilee, P 2022, 'Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases', Journal of Medical Genetics. https://doi.org/10.1136/jmg-2022-108502

TY - JOUR

T1 - Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases

AU - Lakeman, Inge M M

AU - Rodríguez-Girondo, Mar D M

AU - Lee, Andrew

AU - Celosse, Nandi

AU - Braspenning, Merel E

AU - van Engelen, Klaartje

AU - van de Beek, Irma

AU - van der Hout, Annemiek H

AU - Gómez García, Encarna B

AU - Mensenkamp, Arjen R

AU - Ausems, Margreet G E M

AU - Hooning, Maartje J

AU - Adank, Muriel A

AU - Hollestelle, Antoinette

AU - Schmidt, Marjanka K

AU - van Asperen, Christi J

AU - Devilee, Peter

PY - 2022/9/22

Y1 - 2022/9/22

N2 - BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families.METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known.RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM.CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

AB - BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families.METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known.RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM.CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

U2 - 10.1136/jmg-2022-108502

DO - 10.1136/jmg-2022-108502

M3 - Article

C2 - 36137616

SN - 0022-2593

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

ER -