Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry

Key Points

Question

How do previously developed breast cancer polygenic risk scores (PRSs) perform in a clinical setting for women of different ancestries?

Findings

In this multicenter cohort study linking electronic medical records to genotyping data that including 39 591 women, PRSs were significantly associated with breast cancer risk in women of all ancestries, although the effect sizes were smaller in women with African ancestry.

Meaning

Previously developed PRS models for breast cancer risk performed well for women with European and Latinx ancestries in different clinical settings; these results suggest that larger studies are needed to develop and validate PRSs for women with African ancestry.

Abstract

This cohort study of multiple US medical centers with electronic medical records linked to genotype data examines the association of the ancestry of populations used to model polygenic risk scores for breast cancer with their ability to estimate cancer risk for women with different racial/ethnic ancestries.

Abstract

Importance

Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown.

Objective

To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry.

Design, Setting, and Participants

This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm.

Main Outcomes and Measures

Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components.

Results

This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations.

Conclusions and Relevance

This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.