Abstract 5883: Development and testing of a polygenic risk score for proliferative breast cancers
Authors: Shieh Yiwey , Roger Jacquelyn , Huntsman Scott , Hu Donglei , Nierenberg Jovia L. , Kapoor Pooja Middha , Yau Christina , Hirst Gillian , van 't Veer Laura , Esserman Laura 
Published: June 2022

Abstract
Background: Identification of women at elevated risk for highly proliferative, poor prognosis breast cancers could have important implications for screening and prevention. Genome-wide association studies (GWAS) have found &gt;200 single nucleotide polymorphisms (SNPs) associated with breast cancer risk, with many SNPs differentially associated with ER status or intrinsic subtype. We hypothesized that some of these SNPs are preferentially associated with more proliferative tumors, while others are preferentially associated with less proliferative tumors. In this study, we aimed to build a polygenic risk score (PRS) predictive of proliferative tumors, using the GWAS-identified SNPs.
Methods: We used data from 3 studies that included array-based SNP genotyping and tumor transcriptomic data: The Cancer Genome Atlas, METABRIC, and the I-SPY 2 Trial (total n=2,467). Our outcome was the risk of recurrence score weighted on proliferation (ROR-P), a validated tumor prognostic signature. Using the breast cancer risk SNPs, we built respective linear regression models to predict ROR-P, with genetic ancestry, study, and ER status as covariates. We performed 5-fold cross-validation and used the model r2 to identify the optimal p-value threshold for including SNPs in the PRS. To decrease uncertainty of our estimates, we performed 100 repeats across the pooled datasets. To test whether this model predicted poor prognosis breast cancers, we first used it to impute ROR-P among genotyped breast cancer cases in UK Biobank (UKB). We then examined the association between “genetically predicted” ROR-P and breast cancer-specific survival using Cox proportional hazards models adjusted for genetic ancestry and age at diagnosis.
Results: Associations between 224 breast cancer SNPs and ROR-P were tested. The best-performing model in cross-validation contained 96 SNPs, each associated with ROR-P at p &lt; 0.45, with model r2 0.054. The SNPs with the strongest positive correlations with ROR-P included those discovered in GWAS for HER2-positive and ER-negative cancers, both of which tend to be highly proliferative. Among 7,247 incident cancers in UKB, higher genetically predicted ROR-P was associated with shorter survival, with a per-standard deviation hazard ratio of 1.14 (95% CI 1.05-1.24, p = 0.002).
Conclusions: We used breast cancer susceptibility SNPs to construct a PRS fitted to ROR-P, a prognostic signature recapitulating tumor proliferation. This PRS was associated with worse clinical outcomes in breast cancer cases from UKB. Our results suggest that correlations between SNPs and tumor gene expression can be used to “tune” PRS to tumor phenotype, e.g. proliferation. Highly proliferative tumors are more likely to present as advanced cancers even among women getting routine screening. If replicated in other datasets, our findings could be used to identify women who may especially benefit from tailored screening and prevention.
Citation Format: Yiwey Shieh, Jacquelyn Roger, Scott Huntsman, Donglei Hu, Jovia L. Nierenberg, Pooja Middha Kapoor, Christina Yau, Gillian Hirst, Laura van 't Veer, Laura Esserman. Development and testing of a polygenic risk score for proliferative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5883.