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Genetic and Ancestral Determinants of Pathological and Molecular Tumor Immune Phenotypes in A Multi-Ethnic Population of Breast Cancer Patients: An Evolutionary Perspective

Award Number: F30CA294838
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $42,256 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	000	1	8/25/2025	NEW	$42,256
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	001	1	8/25/2025	NEW	$0
														Subtotal = $42,256

Grand Total All Awards = $42,256

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Genetic and Ancestral Determinants of Pathological and Molecular Tumor Immune Phenotypes in A Multi-Ethnic Population of Breast Cancer Patients: An Evolutionary Perspective

Award Number: F30CA294838

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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