OR16-01 A Common WNT4 Polymorphism Drives Gynecologic Cancer Phenotypes And Health Disparities
Authors: Bitler Benjamin G , Shackleford Madeleine T , Treviño Lindsey S , Cook Linda S , Sikora Matthew J 
Published: October 2023

Disclosure: B.G. Bitler: None. M.T. Shackleford: None. L.S. Treviño: None. L.S. Cook: None. M.J. Sikora: None.

Gynecologic cancers such as ovarian cancer (OvCa) are among the deadliest affecting women due to therapy resistance and limited understanding of disease etiology and risk. An underexplored risk factor is Wnt ligand WNT4, which is central to ovarian and uterine organogenesis. A single nucleotide polymorphism at a key WNT4 regulatory site (rs3820282) is associated with 10-25% increased risk for gynecologic pathologies including OvCa but the mechanism is unknown. Our prior work links WNT4 signaling to cancer cell growth, metabolism, and therapy resistance, suggesting the rs3820282 variant activates WNT4 to drive cancer phenotypes. Importantly, rs3820282 variant allele frequency (VAF) is ∼0% in African populations, ∼15% in Caucasians, 20-40% in Latinx populations, and 45-55% in Asian populations, paralleling increased incidence of aggressive OvCa subtypes in Asian populations. We hypothesize the rs3820282 variant drives OvCa health disparities by aberrant activation of WNT4, mediating distinct cancer etiology, therapy resistance, and poor patient outcomes. Supporting this hypothesis, we found WNT4-overexpression in an ID8 murine OvCa model drove cisplatin resistance in vitro, and resistance and metastatic outgrowth in vivo (n=5 mice/model; post-treatment metastatic nodule mass: empty vector = 5±8mg; WNT4 = 42±18mg; p=0.0078). In paired OvCa tumors pre-/post-treatment with neoadjuvant chemotherapy (n=18 pairs), we found WNT4 in the top 10 most-strongly induced genes post-chemotherapy (&gt;4-fold, p =0.0005). In OvCa cell lines, WNT4 siRNA only suppressed growth in WNT4 variant lines (60% reduced growth in n=4 variants, vs n=4 wild-type p=0.010). WNT4 siRNA dysregulated mitochondrial function only in WNT4 variant lines, linking the rs3820282 variant to WNT4-driven metabolic remodeling. We next performed protein array analysis on 103 gynecologic tumors (52% heterozygote+variant); this is one of the largest proteomic studies on gynecologic tissues and the first enriched for patient diversity (47% from non-White patients). We identified differential metabolic signaling; AMPK activation was increased in variant tumors (AMPKα1-pT172 + AMPKα2-pS345; p=0.031) along with AMPK signaling targets. Conversely, glucose metabolism proteins were increased in wild-type tumors, and inversely correlated with AMPK activation (Spearman ρ=-0.34, p=0.0005), suggesting that WNT4 genotype underpins AMPK activation and metabolic remodeling. Taken together, the rs3820282 variant permits aberrant activation of WNT4, driving AMPK-mediated metabolic remodeling and therapy resistance. As the rs3820282 VAF differs widely across populations, WNT4 polymorphism may drive disparities in gynecologic cancer risk and outcomes. Understanding WNT4 signaling and regulation via the rs3820282 variant can lead to precision treatments exploiting cellular dependencies on WNT4 signaling.

Presentation: Friday, June 16, 2023