Genetic and Ancestral Determinants of Pathological and Molecular Tumor Immune Phenotypes in A Multi-Ethnic Population of Breast Cancer Patients: An Evolutionary Perspective - Breast cancer remains the most commonly diagnosed malignancy and the second most common cause of cancer death in women, mostly from disease of aggressive features like estrogen receptor-negative and triple-negative status. The incidence of aggressive breast cancer has been linked to a prolonged pro-inflammatory immune response and dysfunction in the tumor microenvironment (TME). We hypothesize that genetic selection and adaptation to distinct local pathogenic environments during the evolution of different human populations from thousands of years ago have led to genetic differences in host immunity, which contribute to breast cancer disparities. This hypothesis is supported by previous studies that showed genetic estimates of African ancestry are strong predictors of systemic inflammatory response. Moreover, studies from our group have shown that the West African ancestry-linked Duffy-null allele, which confers malaria resistance, has a strong influence on circulating plasma chemokine levels. While these studies provide insight into systemic immunity, the ancestral and genetic determinants of immune phenotypes in the TME are largely unknown. Recent genome-wide association studies (GWAS) have shown that the immune response in the TME is shaped significantly by germline genetics; however, all these GWAS were performed in populations with lower genetic estimates of African ancestry. Thus, it is timely to conduct research to examine immunogenomic factors that shape the TME in patients of different genetic ancestries to better understand the causes of breast cancer disparities. We propose to leverage a rich body of genetic, pathological, and transcriptomic data from > 5,000 women with breast cancer in the context of three large studies. We will 1) perform the first local ancestry-informed GWAS of pathological tumor-infiltrating lymphocytes (TILs) in a group of breast cancer patients. Moreover, we will investigate the role of selection and adaptation in the presence and abundance of TILs by calculating population branch statistics and integrated haplotype scores for significantly associated SNPs. Moreover, we will 2) examine the role of germline genetics and ancestry in the inflammatory state of the TME through a cross-ancestry comparison of inferred immune cell composition, immune gene expression, and quantitative trait loci (QTL) with tumor RNA-seq and matched genotype data from > 1300 women. The results of this proposal will practically be used to decrease disparities in the following ways: 1) Generate the largest publicly available local ancestry-informed expression-QTL/splicing-QTL information for breast cancer tissue for the field. 2) Identify variation in immune response across ancestries that may function as targets for novel immunotherapies or vaccines. Our findings will advance our understanding of the multifaceted mechanisms of cancer health disparities from a novel perspective of genetic ancestry and tumor immunity and may inform clinical investigations of immunotherapy for breast cancer in all women.
