Transcriptome-wide association study of risk of recurrence in Black and White breast cancer patients

BackgroundContinuous risk of recurrence scores (CRS) based on PAM50 gene expression are vital prognostic tools for breast cancer (BC). Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to BC disparities, evidence for biological and germline contributions is emerging. We investigated germline genetic associations with CRS and CRS disparity through a Transcriptome-Wide Association Study (TWAS). MethodsIn the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N=1,043 WW, 1083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; Proliferation Score; ROR-P: ROR-S plus Proliferation Score) on imputed Genetically-Regulated tumor eXpression (GReX). Using Bayesian multivariate regression and adaptive shrinkage, we tested TWAS-significant genes for associations with PAM50 tumor expression and subtype to elucidate patterns of germline regulation underlying TWAS-gene and CRS associations. ResultsAt FDR-adjusted P < 0.10, we detected 7 TWAS-genes among WW and 1 TWAS-gene among BW. Among WW, CRS showed positive associations with MCM10, FAM64A, CCNB2, and MMP1 GReX and negative associations with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower Proliferation score and ROR-P. TWAS-gene and PAM50 tumor expression associations highlighted potential mechanisms for TWAS-gene to CRS associations. ConclusionsAmong BC patients, we find differential germline associations with three CRS by race, underscoring the need for larger, more diverse datasets in molecular studies of BC. Our findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for interpreting CRS in clinical settings.