Abstract 2419: A polygenic risk score predicts breast cancer risk in Latinas
Authors: Shieh Yiwey , Fejerman Laura , Sawyer Sarah D. , Hu Donglei , Huntsman Scott , John Esther M. , Kushi Lawrence H. , Torres-Mejia Gabriela , Weitzel Jeffrey N. , Haiman Christopher A. , Ziv Elad , Neuhausen Susan L. 
Published: August 2019

Abstract
Background: Genome-wide association studies (GWAS) have identified over 180 single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Polygenic risk scores (PRS) represent the combined effects of multiple SNPs and have been consistently shown to improve the performance of existing risk models. Most SNPs were discovered in women of European ancestry. Thus, there are limited data on how PRS perform in Latinas, whose ancestry is a mixture of European and Indigenous American. We therefore sought to validate the performance of a 184-SNP PRS in Latinas.
Methods: We conducted a pooled analysis of U.S. Latina and Mexican participants from 6 existing studies. Our analysis included 3,441 women with breast cancer and 7,773 women without breast cancer. We constructed a PRS containing 184 SNPs associated with breast cancer in prior GWAS, p &lt; 5 x 10-8. We used multivariable logistic regression to evaluate the associations between the PRS and breast cancer, adjusting for genetic ancestry and study of origin. To assess discrimination, we calculated the area under the receiver operating characteristic curve (AUROC). To test the performance of the PRS by genetic ancestry, we stratified our analysis by quartiles of Indigenous American genetic ancestry.
Results: The PRS was associated with breast cancer, with an odds ratio (OR) per standard deviation increment of 1.51 (95% CI 1.44-1.59). The PRS showed intermediate discrimination for cases vs. controls, with an AUROC of 0.62 (95% CI 0.60-0.63). When we stratified the analysis by genetic ancestry, the PRS performed worse in women with higher Indigenous American/lower European ancestry. Specifically, the discrimination of the PRS was least in the top quartile of Indigenous American ancestry and greatest in the bottom quartile, with AUROC of 0.60 (95% CI 0.57-0.62) vs. 0.65 (95% CI 0.62-0.67), respectively (p = 0.01). The corresponding ORs per standard deviation of the PRS were 1.40 (95% CI 1.29-1.53) for the top quartile and 1.70 (95% CI 1.52-1.89) for the bottom quartile of Indigenous American ancestry (p = 0.006).
Conclusions: A 184-SNP PRS predicts breast cancer in Latinas, with the AUROC of 0.62 in our study being comparable to previous estimates in Europeans. However, the performance of the PRS varied according to genetic ancestry. While our results suggest the PRS may be used as-is in Latinas with higher European ancestry, future efforts should focus on refining the PRS in Latinas of higher Indigenous American ancestry through discovery and replication of novel predictive SNPs in this subgroup.
Citation Format: Yiwey Shieh, Laura Fejerman, Sarah D. Sawyer, Donglei Hu, Scott Huntsman, Esther M. John, Lawrence H. Kushi, Gabriela Torres-Mejia, Jeffrey N. Weitzel, Christopher A. Haiman, Elad Ziv, Susan L. Neuhausen. A polygenic risk score predicts breast cancer risk in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2419.