Development and testing of a polygenic risk score for breast cancer aggressiveness

Abstract

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. We used as a measure of aggressiveness an established prognostic signature derived from tumor gene expression, the risk of recurrence score weighted on proliferation (ROR-P). Using 2,363 breast cancers with available ROR-P and single nucleotide polymorphism (SNP) genotypes, we constructed a PRS for aggressiveness based on associations between known breast cancer susceptibility SNPs and ROR-P. In a subsequent meta-analysis of two independent cohorts (785 events in 10,196 breast cancer cases), higher ROR-P PRS was associated with worse breast cancer-specific survival, with a hazard ratio per standard deviation of 1.13 (95% CI 1.05-1.21, p=0.001). The ROR-P PRS provided additional prognostic information to a PRS for estrogen receptor status. These findings show that integrated analysis of germline SNP and tumor gene expression data can enable the construction of PRSs that identify women at higher risk of poor-prognosis breast cancers. This approach could potentially enhance risk stratification for breast cancer screening and prevention.