Differential prevalence of immune-associated germline variants across genetic ancestry groups may partially underlie racial and ethnic disparities in breast cancer outcomes

Introduction: The tumor immune microenvironment (TME) is a strong prognostic factor in breast cancer with higher proportions of tumor infiltrating lymphocytes associated with longer survival. Features of the breast TME vary by race/ethnicity and are linked to disparities in outcomes. In 2021, we performed the first comprehensive investigation of the effect of germline variants on immune traits associated with survival. Leveraging pan-cancer data from The Cancer Genome Atlas (TCGA), we identified 33 heritable immune traits and >1500 SNPs associated with the TME. We hypothesize that racial/ethnic disparities in cancer outcomes may be partially driven by germline SNPs that differentially mediate the TME. Here, we assess the differential expression of heritable immune traits and prevalence of immune-associated germline SNPs across genetic ancestry groups in TCGA breast cancer cohort. Lastly, we assess whether these heritable TME features alone are robust predictors of genetic ancestry. Methods: Utilizing expression-based signatures of immune traits and germline SNP data in TCGA breast cancers (n=986), we investigated the distribution of heritable immune traits and immune-associated germline variants across genetic ancestry groups (European EUR=762, African AFR=163, Asian ASN=45, Amerindian AMR n=16). Differential expression of heritable traits across genetic ancestries were assessed using Kruskal-Wallis test. Proportions of genotypes across genetic ancestries were compared using multiple pair-wise Fisher’s exact tests. P-values were adjusted for multiple testing, and significance defined at adj. p<0.05. Multi-class prediction of EUR, AFR and ASN genetic ancestry was performed using random forest machine learning models. Cross-validation was performed in 75% of samples and 25% used for independent validation. Immune traits and/or germline SNPs were used as features and model performance was evaluated using mean balanced accuracy (Acc). Results: Expression of 33% of heritable immune traits varied by genetic ancestry in breast cancer (adj. p<0.05). Enrichment of eosinophils, natural killer, Th17 and T central memory cells were lower while expression of Interferon, PD-1, and antigen-presentation signatures were higher in AFR vs. EUR. Enrichment of Th2 cells was higher in ASN vs. EUR, while cytotoxic cells was higher in AMR vs. EUR. Moreover, 31% of immune-associated SNPs had significant differences in genotype proportions between at least two ancestry groups. Prevalence of 454 SNPs varied between AFR and EUR and included SNPs associated with CD8 T cells and Interferon signaling. Immune-associated germline SNPs (Acc=0.96) and immune traits+germline SNPs (Acc=0.99) were robust predictors of EUR, AFR and ASN ancestry. Conclusion: Prevalence of heritable components of the TME varied across genetic ancestries. By identifying which features of the TME that drive treatment responses are mediated by heritable germline factors, we can further elucidate mechanisms that underlie disparities in treatment outcomes. Further validation of these findings is underway.