Development and Validation of a Breast Cancer Polygenic Risk Score on the Basis of Genetic Ancestry Composition.
JCO Precis Oncol
washington; renton; genomics; Humans; Female; Breast Neoplasms; Genetic Predisposition to Disease; Genome-Wide Association Study; Risk Factors; Multifactorial Inheritance
PURPOSE: Polygenic risk scores (PRSs) for breast cancer (BC) risk stratification have been developed primarily in women of European ancestry. Their application to women of non-European ancestry has lagged because of the lack of a formal approach to incorporate genetic ancestry and ancestry-dependent variant frequencies and effect sizes. Here, we propose a multiple-ancestry PRS (MA-PRS) that addresses these issues and may be useful in the development of equitable PRSs across other cancers and common diseases.
MATERIALS AND METHODS: Women referred for hereditary cancer testing were divided into consecutive cohorts for development (n = 189,230) and for independent validation (n = 89,126). Individual genetic composition as fractions of three reference ancestries (African, East Asian, and European) was determined from ancestry-informative single-nucleotide polymorphisms. The MA-PRS is a combination of three ancestry-specific PRSs on the basis of genetic ancestral composition. Stratification of risk was evaluated by multivariable logistic regression models controlling for family cancer history. Goodness-of-fit analysis compared expected with observed relative risks by quantiles of the MA-PRS distribution.
RESULTS: In independent validation, the MA-PRS was significantly associated with BC risk in the full cohort (odds ratio, 1.43; 95% CI, 1.40 to 1.46;
CONCLUSION: The MA-PRS uses genetic ancestral composition to expand the utility of polygenic risk prediction to non-European women. Inclusion of genetic ancestry in polygenic risk prediction presents an opportunity for more personalized treatment decisions for women of varying and mixed ancestries.
Women & Children
Hughes, Elisha; Wagner, Susanne; Pruss, Dmitry; Bernhisel, Ryan; Probst, Braden; Abkevich, Victor; Simmons, Timothy; Hullinger, Brooke; Judkins, Thaddeus; Rosenthal, Eric; Roa, Benjamin; Domchek, Susan M; Eng, Charis; Garber, Judy; Gary, Monique; Klemp, Jennifer; Mukherjee, Semanti; Offit, Kenneth; Olopade, Olufunmilayo I; Vijai, Joseph; Weitzel, Jeffrey N; Whitworth, Pat; Yehia, Lamis; Gordon, Ora K; Pederson, Holly; Kurian, Allison; Slavin, Thomas P; Gutin, Alexander; and Lanchbury, Jerry S, "Development and Validation of a Breast Cancer Polygenic Risk Score on the Basis of Genetic Ancestry Composition." (2022). Articles, Abstracts, and Reports. 6830.