Oku, A. | bioRxiv Science

bioRxiv2026

Comprehensive Molecular Characterization of High-Grade Endometrial Cancer in an Ancestrally-Diverse Cohort

Endometrial cancer (EC) exhibits one of the most striking racial disparities in oncology with black women disproportionately affected by aggressive high-grade subtypes that have poorer outcomes. While social and environmental factors undoubtedly contribute, the molecular underpinnings of these disparities remain critically understudied. To bridge this knowledge gap, we performed matched tumor-normal whole-genome sequencing and tumor transcriptome sequencing on 71 predominantly high-grade EC patient samples from an ancestrally diverse cohort of women recruited at a large hospital system in the New York metropolitan area. Our analysis characterized the germline and somatic mutation landscape, identifying ancestry-associated molecular differences. Notably, focal amplification of the EVI1 transcription factor (encoded at the MECOM locus) was significantly more frequent in African ancestry patients and associated with poorer clinical outcomes in an external validation cohort. Additionally transcriptome analysis revealed decreased CD8+ T cell infiltration with increasing African ancestry, suggesting tumor immune microenvironment differences with potential therapeutic implications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/721962v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@12125b9org.highwire.dtl.DTLVardef@133c787org.highwire.dtl.DTLVardef@707af0org.highwire.dtl.DTLVardef@97615c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThis study represents the most ancestrally diverse whole-genome sequencing characterization of high-grade endometrial cancer, with 62% of patients of African ancestry. C_LIO_LIMECOM focal amplification preferentially targets the oncogenic short isoform (EVI1) and is more frequent in patients of African ancestry. C_LIO_LIAfrican ancestry is associated with reduced CD8+ T cell infiltration and differential activation of immune and metabolic pathways in copy-number high endometrial tumors. C_LI

cancer biology↗

bioRxiv2026

A Patient-derived Organoid Platform for Uterine Carcinosarcoma that Emulates Disease Characteristics

Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.

cancer biology↗