Abstract B105: The impact of ancestry on mutational and immune signatures in triple-negative breast cancers

Abstract

Abstract Background: Oncologist found that Androgen Receptor (AR) therapies work in 10% of Triple Negative Breast Cancer (TNBC) patients. Recently we published that women with AR- TNBC, Quadruple Negative Breast Cancer (QNBC), have an Immune basal Signature that’s particularly prevalent in AA women. AA women at a similar mean age of incidence as QNBC AA (47) have increased chances of methylation as a Homologous Recombination Deficiency (HRD) compared to white women. For this reason, we explored QNBC patients to see what correlation may exist between AR, ancestry, immune signatures, and HRD. Methods: We analyzed mRNA expression and HRD events in 987 tumors from The Cancer Genome Atlas. Samples were dichotomized as AR positive or negative using mean gene expression cutoff. Global Ancestry was calculated using Structure. Immune signatures were obtained from TIMER. Mutational Signatures were determined from COSMIC. Linear regression models, forest plots, and Correlation Plots were made using R packages. Pathway analysis was done using the Hallmarks geneset in GSEA and Pathway Studio. Results: Our analysis found significant upregulation of PD-1 (p = 0.001), PD-L1 (p = 0.037), and CTLA-4 (p<0.0001) in QNBC vs non-QNBC patients, as well as upregulated PD-1 (p = 0.017), PD-L1 (p = 0.011), and CTLA-4 (p = 0.0114) in AA QNBC vs CA QNBC using linear regression models adjusted for age and stage. We also found an upregulation in TH-1(p < 0.0001) and TH-17(p <0.0001) differentiation pathways in AA QNBC patients compared to CA QNBC patients found through pathway studio. We also observed that of the 20 AA patients that had an HRD only 2 were mutations while the other 18 were caused by Epigenetic Silencing. We found that West African global ancestry is associated with lower expression of BRCA1 (p = 0.0113), BRCA2 (p < 0.001), RAD51C (p = 0.0208) and, PALB2 (p < 0.001). We also found that within QNBC patients European global ancestry was inversely associated with the APOBEC mutational signature (p = 0.027) and West African global ancestry was inversely associated with the “Aging” mutational signature (p = 0.0256). There was no significant association with global ancestry and the HRD signature. Conclusion: The use of AR as a biomarker may lead to better diagnosis of aggressiveness for breast cancer patients especially for AA women and women with TNBC. QNBC patients may be receptive to immune therapies in particular patients of African Ancestry. Most patients with HRD are likely to be QNBC. West African global ancestry was associated with lower levels of the Aging signature and European global ancestry was associated with lower levels of APOBEC mutational Signature. Also, Women of African Ancestry are more likely to have epigenetically silenced DNA repair mechanism compared to Mutations in it while women of European descent have similar chances of having both. Despite this neither groups global ancestry had a significant association with the HRD mutation signature. Further research is needed to determine the impact of local ancestry on the HRD signature. Citation Format: Raymond W Hughley, Clayton Yates, Paz Polak. The impact of ancestry on mutational and immune signatures in triple-negative breast cancers [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B105.