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The importance of ethnicity: Are breast cancer polygenic risk scores ready for women who are not of White European origin?

ABSTRACT: Polygenic risk scores (PRS) for disease risk stratification show great promise for application in general populations, but most are based on data from individuals of White European origin. We assessed two well validated PRS (SNP18, SNP143) in the Predicting-Risk-of-Cancer-At-Screening (PROCAS) study in North-West England for breast cancer prediction based on ethnicity. Overall, 9475 women without breast cancer at study entry, including 645 who subsequently developed invasive breast cancer or ductal carcinoma in situ provided DNA. All were genotyped for SNP18 and a subset of 1868 controls were genotyped for SNP143. For White Europeans both PRS discriminated well between individuals with and without cancer. For n = 395 Black (n = 112), Asian (n = 119), mixed (n = 44) or Jewish (n = 120) women without cancer both PRS overestimated breast cancer risk, being most marked for women of Black and Jewish origin (P < .001). SNP143 resulted in a potential mean 40% breast cancer risk overestimation in the combined group of non-White/non-European origin. SNP-PRS that has been normalized based on White European ethnicity for breast cancer should not be used to predict risk in women of other ethnicities. There is an urgent need to develop PRS specific for other ethnicities, in order to widen access of this technology.

SUBMITTER: Evans DG

PROVIDER: S-EPMC9290473 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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The importance of ethnicity: Are breast cancer polygenic risk scores ready for women who are not of White European origin?

Evans D Gareth DG van Veen Elke M EM Byers Helen H Roberts Eleanor E Howell Anthony A Howell Sacha J SJ Harkness Elaine F EF Brentnall Adam A Cuzick Jack J Newman William G WG

International journal of cancer 20210907 1

Polygenic risk scores (PRS) for disease risk stratification show great promise for application in general populations, but most are based on data from individuals of White European origin. We assessed two well validated PRS (SNP18, SNP143) in the Predicting-Risk-of-Cancer-At-Screening (PROCAS) study in North-West England for breast cancer prediction based on ethnicity. Overall, 9475 women without breast cancer at study entry, including 645 who subsequently developed invasive breast cancer or duc ...[more]

PMID: 34460111

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Project description:ImportanceMultiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown.ObjectiveTo examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry.Design, setting, and participantsThis 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 measuresMultivariable 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.ResultsThis 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 relevanceThis 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.

Project description:ImportancePolygenic risk scores (PRSs) have shown promise in breast cancer risk prediction; however, limited studies have been conducted among Asian women.ObjectiveTo develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors.Design, setting, and participantsThis diagnostic study included women of Asian ancestry from the Asia Breast Cancer Consortium. PRSs were developed using data from genomewide association studies (GWASs) of breast cancer conducted among 123 041 women with Asian ancestry (including 18 650 women with breast cancer) using 3 approaches: (1) reported PRS for women with European ancestry; (2) breast cancer-associated single-nucleotide variations (SNVs) identified by fine-mapping of GWAS-identified risk loci; and (3) genomewide risk prediction algorithms. A nongenetic risk score (NGRS) was built, including 7 well-established nongenetic risk factors, using data of 416 case participants and 1558 control participants from a prospective cohort study. PRSs were initially validated in an independent data set including 1426 case participants and 1323 control participants and further evaluated, along with the NGRS, in the second data set including 368 case participants and 736 control participants nested within a prospective cohort study.Main outcomes and measuresLogistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% CIs and area under the receiver operating characteristic curve (AUC).ResultsA total of 126 894 women of Asian ancestry were included; 20 444 (16.1%) had breast cancer. The mean (SD) age ranged from 49.1 (10.8) to 54.4 (10.4) years for case participants and 50.6 (9.5) to 54.0 (7.4) years for control participants among studies that provided demographic characteristics. In the prospective cohort, a PRS with 111 SNVs developed using the fine-mapping approach (PRS111) showed a prediction performance comparable with a genomewide PRS that included more than 855 000 SNVs. The OR per SD increase of PRS111 score was 1.67 (95% CI, 1.46-1.92), with an AUC of 0.639 (95% CI, 0.604-0.674). The NGRS had a limited predictive ability (AUC, 0.565; 95% CI, 0.529-0.601). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and NGRS were at a 3.84-fold (95% CI, 2.30-6.46) and 2.10-fold (95% CI, 1.22-3.62) higher risk of breast cancer, respectively. The prediction model including both PRS111 and NGRS achieved the highest prediction accuracy (AUC, 0.648; 95% CI, 0.613-0.682).Conclusions and relevanceIn this study, PRSs derived using breast cancer risk-associated SNVs had similar predictive performance in Asian and European women. Including nongenetic risk factors in models further improved prediction accuracy. These findings support the utility of these models in developing personalized screening and prevention strategies.

Project description:Polygenic risk scores (PRS) have predominantly been derived from genome-wide association studies (GWAS) conducted in European ancestry (EUR) individuals. In this study, we present an in-depth evaluation of PRS based on multi-ancestry GWAS for five cardiometabolic phenotypes in the Penn Medicine BioBank (PMBB) followed by a phenome-wide association study (PheWAS). We examine the PRS performance across all individuals and separately in African ancestry (AFR) and EUR ancestry groups. For AFR individuals, PRS derived using the multi-ancestry LD panel showed a higher effect size for four out of five PRSs (DBP, SBP, T2D, and BMI) than those derived from the AFR LD panel. In contrast, for EUR individuals, the multi-ancestry LD panel PRS demonstrated a higher effect size for two out of five PRSs (SBP and T2D) compared to the EUR LD panel. These findings underscore the potential benefits of utilizing a multi-ancestry LD panel for PRS derivation in diverse genetic backgrounds and demonstrate overall robustness in all individuals. Our results also revealed significant associations between PRS and various phenotypic categories. For instance, CAD PRS was linked with 18 phenotypes in AFR and 82 in EUR, while T2D PRS correlated with 84 phenotypes in AFR and 78 in EUR. Notably, associations like hyperlipidemia, renal failure, atrial fibrillation, coronary atherosclerosis, obesity, and hypertension were observed across different PRSs in both AFR and EUR groups, with varying effect sizes and significance levels. However, in AFR individuals, the strength and number of PRS associations with other phenotypes were generally reduced compared to EUR individuals. Our study underscores the need for future research to prioritize 1) conducting GWAS in diverse ancestry groups and 2) creating a cosmopolitan PRS methodology that is universally applicable across all genetic backgrounds. Such advances will foster a more equitable and personalized approach to precision medicine.

Dataset Information

The importance of ethnicity: Are breast cancer polygenic risk scores ready for women who are not of White European origin?

Publications

The importance of ethnicity: Are breast cancer polygenic risk scores ready for women who are not of White European origin?

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