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. 2025 Jul:198:75-83.
doi: 10.1016/j.ygyno.2025.05.010. Epub 2025 May 30.

Molecular diversity in uterine carcinosarcoma: Beyond TP53

Eveline N B Pham  1 , Caroline B van den Berg  2 , Nina C C J Kokke  3 , Ronald van Marion  4 , Dennis Dollée  5 , Ingrid A Boere  6 , Floris H Groenendijk  7 , Heleen J van Beekhuizen  8
Affiliations

Molecular diversity in uterine carcinosarcoma: Beyond TP53

Eveline N B Pham et al. Gynecol Oncol. 2025 Jul.

Abstract

Objective: This study conducted genomic profiling of uterine carcinosarcoma (UCS) to gain molecular insights, analyzing carcinoma and sarcoma components separately when possible.

Methods: Clinical and pathological data from UCS patients were collected, and tumor DNA was analyzed using next-generation sequencing to evaluate genomic alterations, microsatellite instability, tumor mutational burden (TMB), and homologous recombination deficiency (HRD). Gene alterations were investigated within relevant cancer pathways, and the therapeutic potential was assessed. Lastly, univariate Cox regression analyses estimated hazard ratios.

Results: Among 51 included patient, TP53 was most frequently altered (88 %), followed by PIK3CA (35 %) and CCNE1 (33 %). Separate analysis of carcinoma and sarcoma components revealed concordant gene variants but divergent copy number variations. Based on molecular classification, the majority of the cases 44 (84.6 %) had a TP53mutant profile. Additionally, 11 cases were HR deficient, and 7 samples (14 %) had high TMB (≥16). Key altered pathways were TP53, RTK/RAS, PI3K, and cell cycle pathways. Altogether, alterations that could serve as possible molecular targets for existing therapies were identified in 45 cases (88 %). No molecular variables was statistical significant in the survival analysis.

Conclusion: Although, the TP53-mutant profile was the most common subtype, UCS remains molecularly heterogeneous, revealing potential targets for existing therapies and emphasizing the role of molecular profiling in guiding treatment in UCS. Our comparison of the carcinoma and sarcoma components confirms a monoclonal origin. Despite its molecular heterogeneity, these findings highlight potential targets for existing therapies and emphasize the role of molecular sequencing in guiding treatment in UCS.

Keywords: Endometrial cancer; Molecular analysis; Next-generation sequencing; Rare cancers; Targeted therapy; Uterine carcinosarcoma.

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Conflict of interest statement

Declaration of competing interest The authors have no conflict of interest.