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PROJECT ABSTRACT- Overall The University of Chicago has active clinical, basic and population science programs and thriving translational research programs. The goal of the UChicago Interdisciplinary Cancer Health Disparities SPORE is to reduce global disparities in cancer outcomes by developing the platform to apply novel approaches to the prevention, diagnosis and treatment of cancers exhibiting disparities in incidence or outcomes among US Minority populations. We leverage our institutional strengths in emerging new fields of science including bioinformatics, genomics therapeutics, human genetics, immunology, medical oncology and statistical genetics. These advantages, together with our location in the ethnically diverse south side of Chicago and our exciting new partnerships in the UChicago Institute for Translational Medicine, make this a truly unique SPORE program. Our overall goals are in two interrelated thematic areas with specific aims, Aim 1) To find novel ways to make chemotherapy more effective for patients with aggressive cancers. Project 1: Integrating Tumor Genomic and Gut Microbiome Analyses to Close Breast Cancer Mortality Gap will use a highly innovative approach to extend our understanding of the biologic basis of breast cancer progression by performing deep whole exome sequenicng (WES) of 500 well-phenotyped tumors to identify somatic mutation signatures. This intimate association between the gut mucosa and the resident microbial community facilitates immune responses against invading pathogens and tolerance to beneficial microbes and may influence tumor progression and how patients respond to chemotherapy. We will recruit 750 new breast cancer patients and collect stool for Microbiome Wide Association Study in 140 patients receiving neoadjuvant chemotherapy to determine whether fecal microbial biomarkers are predictive of response to neoadjuvant chemotherapy; Aim 2) To personalize risk prediction for prevention and treatment of aggressive cancers. Project 2- Personalized Risk-based Imaging Surveillance Model (PRISM) for High Risk Women will examine whether ethnic specific Polygenic Risk Score (PRS) can stratify women into risk categories and subsequently used in the clinic to personalize culturally tailored risk-reducing interventions. We will test the hypothesis that state-of- the-art genomic testing combined with state-of-the-art Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) techniques can comprehensively characterize early breast cancers, and provide effective and affordable strategies for risk adapted management of mutation carriers in diverse populations.