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

GEMO Study Collaborators; Daniel R Barnes; Matti A Rookus; Lesley McGuffog; Liene Ņikitina-Zaķe

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

GEMO Study Collaborators, Daniel R Barnes (Member of the Working Group), Matti A Rookus (Member of the Working Group), Lesley McGuffog (Member of the Working Group), Liene Ņikitina-Zaķe (Member of the Working Group)

Research output: Contribution to journal › Article › 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.

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
Externally published	Yes

Field of Science*

3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

UN SDGs

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

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Polygenic risk scores and breast and epithelial ovarian cancerFinal published version, 671 KBLicence: CC BY

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@article{6cc8d658aa2348a9a7ca511706948617,

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 = "{GEMO Study Collaborators} and 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 Domchek, {Susan M} and Liene Ņikitina-Zaķe",

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 = "Lippincott Williams and Wilkins Ltd.",

number = "10",

}

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. / GEMO Study Collaborators; Barnes, Daniel R (Member of the Working Group); Rookus, Matti A (Member of the Working Group) et al.
In: Genetics in Medicine, Vol. 22, No. 10, 10.2020, p. 1653-1666.

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

TY - JOUR

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

AU - GEMO Study Collaborators

A2 - Barnes, Daniel R

A2 - Rookus, Matti A

A2 - McGuffog, Lesley

A2 - Leslie, Goska

A2 - Mooij, Thea M

A2 - Dennis, Joe

A2 - Mavaddat, Nasim

A2 - Adlard, Julian

A2 - Ahmed, Munaza

A2 - Aittomäki, Kristiina

A2 - Andrieu, Nadine

A2 - Andrulis, Irene L

A2 - Arnold, Norbert

A2 - Arun, Banu K

A2 - Azzollini, Jacopo

A2 - Balmaña, Judith

A2 - Barkardottir, Rosa B

A2 - Barrowdale, Daniel

A2 - Benitez, Javier

A2 - Berthet, Pascaline

A2 - Białkowska, Katarzyna

A2 - Blanco, Amie M

A2 - Blok, Marinus J

A2 - Bonanni, Bernardo

A2 - Boonen, Susanne E

A2 - Borg, Åke

A2 - Bozsik, Aniko

A2 - Bradbury, Angela R

A2 - Brennan, Paul

A2 - Brewer, Carole

A2 - Brunet, Joan

A2 - Buys, Saundra S

A2 - Caldés, Trinidad

A2 - Caligo, Maria A

A2 - Campbell, Ian

A2 - Christensen, Lise Lotte

A2 - Chung, Wendy K

A2 - Claes, Kathleen B M

A2 - Colas, Chrystelle

A2 - Collonge-Rame, Marie-Agnès

A2 - Cook, Jackie

A2 - Daly, Mary B

A2 - Davidson, Rosemarie

A2 - de la Hoya, Miguel

A2 - de Putter, Robin

A2 - Delnatte, Capucine

A2 - Devilee, Peter

A2 - Diez, Orland

A2 - Ding, Yuan Chun

A2 - Domchek, Susan M

A2 - Ņikitina-Zaķe, Liene

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.

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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 -

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

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