Evaluation of three polygenic risk score models for the prediction of breast cancer risk in Singapore Chinese

Abstract

Genome-wide association studies (GWAS) have proven highly successful in identifying single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. The majority of these studies are on European populations, with limited SNP association data in other populations. We genotyped 51 GWAS-identified SNPs in two independent cohorts of Singaporean Chinese. Cohort 1 comprised 1294 BC cases and 885 controls and was used to determine odds ratios (ORs); Cohort 2 had 301 BC cases and 243 controls for deriving polygenic risk scores (PRS). After age-adjustment, 11 SNPs were found to be significantly associated with BC risk. Five SNPs were present in <1% of Cohort 1 and were excluded from further PRS analysis. To assess the cumulative effect of the remaining 46 SNPs on BC risk, we generated three PRS models: Model-1 included 46 SNPs; Model-2 included 11 statistically significant SNPs; and Model-3 included the SNPs in Model-2 but excluded SNPs that were in strong linkage disequilibrium with the others. Across Models-1, -2 and -3, women in the highest PRS quartile had the greatest ORs of 1.894 (95% CI = 1.157–3.100), 2.013 (95% CI = 1.227–3.302) and 1.751 (95% CI = 1.073–2.856) respectively, suggesting a direct correlation between PRS and BC risk. Given the potential of PRS in BC risk stratification, our findings suggest the need to tailor the selection of SNPs to be included in an ethnic-specific PRS model.

European polygenic risk score for prediction of breast cancer shows similar performance in Asian women

“…We compared the predictive performance of the 287-SNP PRS for overall breast cancer with five PRSs 15 , 17 , 19 , 26 , 27 , which were previously developed or evaluated using data from Asian populations. Of these 5 PRSs, one was developed using iCogs genotyped studies in BCAC and 744 samples from MyBrCa study 15 .…”

“…We compared the predictive performance of the European ancestry-based PRS with PRSs that were previously developed or evaluated in Asian populations. The five Asian ancestry-derived PRSs included 5 SNPs 15 , 51 SNPs 17 , 44 SNPs 19 , 6 SNPs 26 and 46 SNPs 27 . The PRSs were derived using Eq.…”

“…Although there have been several efforts to create an Asianspecific PRS, these have been limited by the smaller sample size of Asian genetic studies [15][16][17][18][19] . Only~20% of the existing breast cancer genome-wide association study (GWAS) data are from women of Asian ancestry 20,21 .…”

Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE)

“…Lastly, our analysis was restricted to survivors of European ancestry and thus there is a need to assess risk associated with rare P/LP mutations and common variants (i.e. PRS) within other non-European ethnic groups(19–22).…”

Breast Cancer Risk Prediction in Korean Women: Review and Perspectives on Personalized Breast Cancer Screening

“…In addition, there are some studies that showed that PRS can improve the discrimination in Asian women above existing risk models [ 56 58 59 60 61 ]. For example, Shieh et al showed that a PRS comprised of 76 SNPs improved the AUC of the BCSC model in East Asian women in San Francisco, California from 0.62 (95% CI, 0.59–0.66) to 0.72 (95% CI, 0.62–0.82) [ 48 ].…”