PROJECT SUMMARY/ABSTRACT Gynecologic malignancies such as ovarian cancer (OvCa) are among the deadliest cancers affecting women due to therapy resistance and limited understanding of disease etiology and risk. An under-explored risk factor is Wnt ligand WNT4, which is central to ovarian organogenesis. Over 20 studies link WNT4 polymorphisms with increased risk for gynecologic pathologies; one polymorphism at a key WNT4 regulatory site (rs3820282) is associated with 10-25% increased risk for OvCa, but the mechanism(s) is unknown. Our work links WNT4 to cancer cell growth, metabolism, and therapy resistance. We find WNT4 over-expression is sufficient to mediate chemotherapy resistance in vitro, and resistance with increased metastatic outgrowth in vivo, and that WNT4 expression is strongly induced in OvCa cells surviving neoadjuvant chemotherapy. Importantly, the rs3820282 variant allele in the WNT4 regulatory site creates a binding site for nuclear receptor-class transcription factors. CRISPR knock-in of the rs3820282 variant in mice increases Wnt4 expression in gynecologic tissues. Accordingly, in a protein array study of more than 100 OvCa tumor tissues, we found that AMPK activation and downstream signaling were increased in variant allele tumors. Conversely, glucose metabolism proteins were increased in wild-type tumors and inversely correlated with AMPK signaling, suggesting WNT4 genotype underpins metabolic remodeling. These observations suggest that the rs3820282 variant activates WNT4 to drive cancer phenotypes. However, the rs3820282 variant allele frequency (VAF) is widely divergent across ethnic populations, occurring at ~0% in African populations, ~15% in Caucasians, 20-40% in Latinx populations, and 45-55% in Asian populations, paralleling high incidence of aggressive, treatment-resistance OvCa subtype clear cell carcinoma (CCC) in Asian populations. Our goal is to determine how rs3820282 mediates disparities in ovarian cancer outcomes, mechanistically define genotype-driven tumor etiology, and identify therapies to exploit dependence on WNT4. Toward this goal, we will: 1) define how the rs3820282 variant activates WNT4-dependent metabolic remodeling; 2) define rs3820282-driven tumorigenesis and therapeutic response in a model of ovarian clear cell carcinoma (CCC); 3) determine how rs3820282 genotype impacts outcomes for patients with OvCa. With a foundation of rigorous supporting data from human specimens, we will undertake highly mechanistic studies to define the contribution of this common polymorphism to a cancer disparity, tumor metabolic reprogramming, gynecologic tumorigenesis, treatment response, and patient outcomes. We will leverage cutting-edge global metabolomics, tumorigenesis modeling, and human survival studies. Our approach can define the genotype-to-phenotype link, determine how this SNP drives OvCa cancer disparities, and identify approaches to exploit the underlying biology.