Incorporating Alternative Polygenic Risk Scores into the BOADICEA Breast Cancer Risk Prediction Model
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Background: The multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA. Methods: The mean, SD, and proportion of the overall polygenic component explained by the PRS (α2) need to be estimated. a was estimated using logistic regression, where the age-specific log-OR is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component. Results: Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates a, as compared with the RL estimates. The RL a estimates were very close to those obtained by assuming proportionality to the OR per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean. Conclusions: BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model. Impact : The methods described facilitate comprehensive breast cancer risk assessment.
| Original language | English |
|---|---|
| Journal | Cancer Epidemiology Biomarkers and Prevention |
| Volume | 32 |
| Issue number | 3 |
| Pages (from-to) | 422-427 |
| Number of pages | 6 |
| ISSN | 1055-9965 |
| DOIs | |
| Publication status | Published - 2023 |
Bibliographical note
Funding Information:
BCAC is funded by the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and the PERSPECTIVE I&I project. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the NCI Intramural Research Program, NIH.
Funding Information:
N. Mavaddat reports grants from CRUK (PRPGM-Nov20\100002); and grants from the PERSPECTIVE program during the conduct of the study. A. Lee reports other support from Illumina, Inc., outside the submitted work; and is an ‘inventor’ of the BOADICEA model that is licensed by Cambridge Enterprise (part of Cambridge University) for commercial use, for which he receives royalties. A.P. Cunningham reports personal fees from Cambridge Enterprise during the conduct of the study. R.K. Schmutzler reports grants from German Cancer Aid; and grants from Federal Ministry of Education and Research during the conduct of the study; personal fees from AstraZeneca, MSD; and personal fees from GSK outside the submitted work. T.L. Stockley reports personal fees from Janssen, Bayer, Pfizer, Merck; and personal fees from AstraZeneca outside the submitted work. L. Feliubadaló reports personal fees from AstraZeneca outside the submitted work. J. Balmaña reports personal fees and nonfinancial support from AstraZeneca; nonfinancial support from Pfizer; and nonfinancial support from Lilly outside the submitted work. J. Simard reports grants from Genome Canada/Canadian Institutes of Health Research (CIHR)/Genome Québec/Quebec Breast Cancer Foundation/Ontario Research Fund during the conduct of the study. A.C. Antoniou reports grants from Cancer Research UK during the conduct of the study; and BOADICEA is licensed for commercial purposes by Cambridge Enterprise. D.F. Easton reports grants from Cancer Research UK, Genome Canada; and grants from Canadian Institutes of Health Research during the conduct of the study; and the BOADICEA model has been licensed to Cambridge Enterprise for commercialization. Dr. Easton is listed as an inventor. No disclosures were reported by the other authors.
Funding Information:
This work has been supported by grants from Cancer Research UK (PPRPGM-Nov20\100002); the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement numbers 633784 (B-CAST) and 634935 (BRIDGES); the PERSPECTIVE I&I project which is funded by the Government of Canada through Genome Canada (#13529) and the Canadian Institutes of Health Research (#155865), the Ministère de l’Économie et de l’Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation, the CHU de Quebec Foundation and the Ontario Research Fund; and by the NIHR Cambridge Biomedical Research Centre (BRC-1215–20014).
Publisher Copyright:
© 2023 The Authors.
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