Pham Eveline N B, van den Berg Caroline B, Kokke Nina C C J, van Marion Ronald, Dollée Dennis, Boere Ingrid A, Groenendijk Floris H, van Beekhuizen Heleen J
Department of Gynecologic Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands.
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Gynecol Oncol. 2025 Jul;198:75-83. doi: 10.1016/j.ygyno.2025.05.010. Epub 2025 May 30.
This study conducted genomic profiling of uterine carcinosarcoma (UCS) to gain molecular insights, analyzing carcinoma and sarcoma components separately when possible.
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.
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.
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.
本研究对子宫癌肉瘤（UCS）进行基因组分析以获得分子层面的见解，尽可能分别分析癌和肉瘤成分。
收集UCS患者的临床和病理数据，使用二代测序分析肿瘤DNA，以评估基因组改变、微卫星不稳定性、肿瘤突变负荷（TMB）和同源重组缺陷（HRD）。在相关癌症通路中研究基因改变，并评估其治疗潜力。最后，单因素Cox回归分析估计风险比。
在纳入的51例患者中，TP53改变最为常见（88%），其次是PIK3CA（35%）和CCNE1（33%）。对癌和肉瘤成分的单独分析显示基因变异一致，但拷贝数变异不同。基于分子分类，大多数病例44例（84.6%）具有TP53突变型。此外，11例存在HR缺陷，7个样本（14%）具有高TMB（≥16）。关键改变的通路是TP53、RTK/RAS、PI3K和细胞周期通路。总共在45例（88%）中鉴定出可作为现有疗法可能分子靶点的改变。在生存分析中没有分子变量具有统计学意义。
虽然TP53突变型是最常见的亚型，但UCS在分子层面仍具有异质性，揭示了现有疗法的潜在靶点，并强调了分子分析在指导UCS治疗中的作用。我们对癌和肉瘤成分的比较证实了单克隆起源。尽管其分子具有异质性，但这些发现突出了现有疗法的潜在靶点，并强调了分子测序在指导UCS治疗中的作用。
