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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

Lakeman, I.M.M. ; Borg, Åke LU and Schmidt, Marjanka K. (2021) In Genetics in Medicine 23(9). p.1726-1737
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... (More)
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. © 2021, The Author(s). (Less)
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Contribution to journal
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published
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keywords
adult, age, Article, breast cancer, cancer risk, clinical feature, cohort analysis, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, European, family history, female, genetic association, genetic risk score, genetic variability, genotype, heterozygosity, human, major clinical study, prediction, prevalence, retrospective study, risk factor, tumor suppressor gene, breast tumor, genetic predisposition, genetics, heterozygote, mutation, BRCA1 protein, BRCA1 protein, human, BRCA2 protein, BRCA2 protein, human, Adult, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Retrospective Studies, Risk Factors
in
Genetics in Medicine
volume
23
issue
9
pages
12 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85115935642
  • pmid:34113011
ISSN
1098-3600
DOI
10.1038/s41436-021-01198-7
language
English
LU publication?
yes
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faf13419-cb21-4fd6-8186-168abfceac85
date added to LUP
2021-12-28 10:48:45
date last changed
2022-04-27 07:00:45
@article{faf13419-cb21-4fd6-8186-168abfceac85,
  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 &lt; 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. © 2021, The Author(s).}},
  author       = {{Lakeman, I.M.M. and Borg, Åke and Schmidt, Marjanka K.}},
  issn         = {{1098-3600}},
  keywords     = {{adult; age; Article; breast cancer; cancer risk; clinical feature; cohort analysis; estrogen receptor negative breast cancer; estrogen receptor positive breast cancer; European; family history; female; genetic association; genetic risk score; genetic variability; genotype; heterozygosity; human; major clinical study; prediction; prevalence; retrospective study; risk factor; tumor suppressor gene; breast tumor; genetic predisposition; genetics; heterozygote; mutation; BRCA1 protein; BRCA1 protein, human; BRCA2 protein; BRCA2 protein, human; Adult; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Mutation; Retrospective Studies; Risk Factors}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1726--1737}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Genetics in Medicine}},
  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}},
  url          = {{http://dx.doi.org/10.1038/s41436-021-01198-7}},
  doi          = {{10.1038/s41436-021-01198-7}},
  volume       = {{23}},
  year         = {{2021}},
}