Abstract 3264: Epidemiology meets novel transcriptomics in poorly differentiated endometrial carcinomas

Abstract Background: Endometrial cancer (EC) is the commonest gynecological malignancy in high-income settings and is traditionally divided into estrogen-related Type I and non-estrogenic Type II diseases. Type II histologies carry a poorer prognosis and have been under-characterized molecularly in African populations. South African EC data are sparse and largely extrapolated from international cohorts. This study addresses epidemiologic and transcriptomic gaps by profiling clinical outcomes and RNA-level alterations in South African women with epithelial EC, with emphasis on Black females and comparison to African American datasets. Materials and Methods: Retrospective review of 290 electronic health records (2009-2019) from Inkosi Albert Luthuli Central Hospital to determine incidence, FIGO stage distribution, and survival for epithelial EC. Molecular profiling of 76 poorly differentiated FFPE tumor specimens: total RNA extraction, short-read RNA sequencing, alignment with STAR, quantification with featureCounts/StringTie. Analyses included differential gene expression (|log2FC| ≥ 1.0), alternative-splicing (ΔPSI), novel-isoform discovery, and Reactome pathway enrichment to define dysregulated pathways. Publicly available African American datasets were used for cross-population comparisons. Results: Type II histologies comprised 47.9% of cases and aligned with advanced FIGO stage and median overall survival of 3.7 months. Transcriptome analysis revealed a dual signature: upregulation of MAPK/ERK and retinoic-acid pathways (e.g., MKNK2 +2.03 log2FC, RARA +2.14) alongside repression of RNA-Pol II transcription and cell-cycle regulators (e.g., ZNF793 −5.26, MYC −4.50). Exon-skipping in GJA1 and widespread intron retention marked splicing rewiring. StringTie uncovered novel lncRNA and zinc-finger isoforms (e.g., LINC01605), two layers absent from existing annotations. Cross-population analysis confirmed key shared drivers of the copy-number-high/p53-abnormal subtype, while novel splicing variants emerged as population-specific. Conclusion: These findings validate the predominance and aggressiveness of Type II endometrial carcinoma in South African women. The study reveals unique transcriptomic and splicing landscapes in Black females that extend TCGA subtyping. Novel kinase and lncRNA targets (MKNK2, SRPK1, LINC01605) hold promise for tailored therapeutics. Integrating molecular classification into national guidelines, bolstering diagnostic infrastructure, and launching precision-medicine trials will be essential to narrow survival disparities and deliver equitable, biomarker-driven care. Citation Format: Thulo Molefi, Motshedisi Sebitloane, Zodwa Dlamini. Epidemiology meets novel transcriptomics in poorly differentiated endometrial carcinomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3264.