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  • Genomic Alterations and Their Role in the Management of Uterine Carcinosarcoma: Focus on TP53 and Biomarker-Guided Therapy

  • Hatameh fallah,1 Mahdieh Akbarpour Samakoush,2 Mahtab Maleki,3,*
    1. University of Semnan
    2. University of Semnan
    3. Department of Biology, SR.C., Islamic Azad University,Tehran, Iran


  • Introduction: Uterine carcinosarcoma (UCS) is a rare, highly aggressive malignancy composed of carcinomatous and sarcomatous components, with substantial molecular heterogeneity and poor outcomes. TP53 alterations are reported in approximately 80–90% of cases and represent a major genomic feature of UCS. This study reviewed major genomic alterations in UCS and evaluated the role of molecular profiling in prognosis and therapeutic management.
  • Methods: Published studies addressing genomic alterations, molecular classification, clonal origin, and treatment outcomes in UCS were reviewed. Studies using next-generation sequencing, whole-exome/genome sequencing, immunohistochemistry, and clinical outcome analyses were prioritized. Particular attention was given to TP53 alterations, co-occurring genomic changes, molecular profiles, and biomarkers with potential therapeutic utility.
  • Results: TP53 alterations were identified in the majority of UCS cases. High genomic concordance between carcinomatous and sarcomatous components supports a monoclonal origin and the metaplastic carcinoma model of UCS development. Recurrent alterations include PIK3CA, PTEN, PPP2R1A, FBXW7, and KRAS, with amplifications involving MYC and CCNE1. These alterations affect the PI3K/AKT, RTK/RAS, and cell-cycle pathways, highlighting potential therapeutic targets. A recent study identified TP53 alterations in 88% of cases, a TP53-mutant molecular profile in 84.6%, and potentially targetable alterations in 88% [1]. TP53-mutant tumors were the predominant group and showed poorer survival than POLE-mutant tumors. However, POLE-mutant tumors are rare and their prognostic significance requires further validation. Assessment of p53, MMR/MSI, HER2, and comprehensive NGS may help identify patients potentially eligible for biomarker-guided therapies, including HER2-directed treatment and immune checkpoint inhibition.
  • Conclusion: TP53 alterations are a major component of the genomic architecture of UCS and are associated with aggressive disease. However, co-occurring alterations in PI3K/AKT, RTK/RAS, and cell-cycle pathways support the need for comprehensive genomic profiling. Genetic concordance between carcinomatous and sarcomatous components supports a common clonal origin. Integrating genomic profiling with p53, MMR/MSI, and HER2 assessment may improve risk stratification and treatment selection. Given the rarity of UCS and limited disease-specific clinical evidence, prospective multicenter studies are needed to validate biomarkers and develop more precise therapeutic strategies.
  • Keywords: Uterine carcinosarcoma; genomic alterations; TP53; p53-abnormal; molecular classification; next-gene

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