Abstract PO-148: Germline-genome regulated tumor gene expression in relation to risk of recurrence scores in White and Black breast cancer populations

Background: Black women have disproportionately higher incidences of Basal-like breast cancer; prior work in the Carolina Breast Cancer Study (CBCS) has also identified higher ROR in Black women among clinically-defined hormone receptor (HR) positive, HER2 negative patients. Tumor expression-based scores of risk of recurrence (ROR) are vital prognostic tools. Investigation of germline genetic variation in relation to ROR by race strata (White, Black) may offer insight into racially divergent ROR patterns. Methods: From a panel of 417 breast-cancer related genes, we identified 46 genes (Black) and 57 genes (White) with significant cis- heritability and high cross-validation prediction performance in race-specific predictive models of tumor expression from germline genotype. We performed race- specific (N=1,043 White, N=1,083 Black) multivariable linear regression of imputed germline genotype-regulated tumor gene expression (GReX) against ROR scores (ROR-S, Proliferation, ROR-P), adjusting for age, HR status, stage, and CBCS phase as well as multiple tests via the Benjamini-Hochberg procedure. We further performed permutation testing of adjusted R^2 of significant GReX genes against covariate (age, HR, stage, phase) residualized ROR scores. Lastly, we performed race-specific multinomial logistic regression for significant GReX genes against PAM50 expression based BC subtypes. Results: Among White women, GReX of MCM10, FAM64A, NDC80, CCNB2, MMP1, VAV3, PCSK6, and GNG11 was positively associated with ROR while GReX of VAV3, PCSK6, and GNG11 was negatively associated with ROR. Congruent with this observation, GReX of the higher and lower ROR gene sets were associated with significantly increased and decreased odds of Basal-like BC (ref. Luminal A), respectively (e.g. MCM10 odds ratio (OR) and 95% confidence interval (CI): 1.42 [1.18, 1.71]; VAV3 OR and 95% CI: 0.75 [0.63, 0.90]). Similar, but lesser effects were seen for the higher and lower ROR GReX sets for HER2 and Luminal B subtype (ref. Luminal A). Among Blacks, only MMP1 GReX predicted Proliferation and ROR-P, but not ROR-S. MMP1 GReX was found to lower Proliferation and ROR-P, contrary to findings among Whites. Conclusions: We show that GReX of non-PAM50 genes can predict ROR scores and that this relationship may partly be a consequence of non-PAM50 GReX influencing intrinsic BC subtype propensities. Differences in GReX-ROR relationships across race may be informative towards racial differences in ROR scores, underlying tumor molecular signature, and subsequent clinical outcomes. Citation Format: Achal Patel, Arjun Bhattacharya, Melissa Troester, Michael Love. Germline-genome regulated tumor gene expression in relation to risk of recurrence scores in White and Black breast cancer populations [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-148.