{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:23:14Z","timestamp":1790047394028,"version":"4.0.1"},"reference-count":39,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"6","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precision Oncology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>MATERIALS AND METHODS<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> 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; P = 8.6 \u00d7 10<jats:sup>\u2013308<\/jats:sup>) and within each major ancestry. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec>","DOI":"10.1200\/po.22.00084","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T19:59:36Z","timestamp":1667505576000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":23,"title":["Development and Validation of a Breast Cancer Polygenic Risk Score on the Basis of Genetic Ancestry Composition"],"prefix":"10.1200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3145-3913","authenticated-orcid":false,"given":"Elisha","family":"Hughes","sequence":"first","affiliation":[{"name":"Myriad Genetics, Inc, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Wagner","sequence":"additional","affiliation":[{"name":"Myriad Genetics, Inc, Salt Lake City, 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