阐明子宫癌肉瘤的分化生物学

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-08-23 DOI:10.1016/j.tranon.2025.102506

Vikas Garg , Stephenie D. Prokopec , Simone C. Stone , Sara Pakbaz , Min Li Chen , Bernard Lam , Czin Czin Benito , Michelle Mcmullen , Ilinca Lungu , Samanta Del Rossi , Anthony Msan , Valerie Bowering , Valentin Sotov , Christine Tran , Marcus O. Butler , Amit M. Oza , Phedias Diamandis , Ben X. Wang , Stephanie Lheureux

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引用次数: 0

摘要

目的子宫癌肉瘤（UCS）是一种以上皮(C)和间充质(S)成分为特征的侵袭性恶性肿瘤，生物学复杂，治疗反应差。本研究旨在通过基因组学、表观基因组学和转录组学分析来加深对UCS的理解。方法对微解剖（C和S）肿瘤标本进行全基因组测序（WGS）、rna测序和酶甲基化测序（EM-Seq）。采用多重免疫组织化学（mIHC）和计算病理学技术评估肿瘤微环境（TME）。结果来自9例患者的18份样本的swgs和EM-seq显示肿瘤突变负荷低（TMB，中位数= 0.97个突变/Mb），无微卫星不稳定性（MSI）证据。在TP53（94%）、PIK3CA（33%）和PPP2R1A（22%）中发现了驱动突变。拷贝数（CN）分析显示MYC（67%）、PIK3CA（61%）、CCNE1（56%）、AKT2（44%）和SMARCA4（39%）的重复扩增。对比分析显示，C区和S区在突变频率、CN、转录组和甲基组谱方面没有显著差异。这两个区域都表现出整体的低甲基化，C区域的异种代谢途径和S区域的上皮-间质转化途径的功能富集。21例患者的比较mIHC显示T细胞和B细胞密度相似，但S组分中肿瘤相关巨噬细胞和PD-L1+细胞密度更高。计算形态学分析显示，UCS病例内和病例间存在大量的组织形态学异质性。通过阐明上皮和间充质成分之间复杂的相互作用，本研究增强了我们对UCS的理解，并为开发针对基因组改变和TME的新治疗策略提供了信息。

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Elucidating divergent biology in uterine carcinosarcoma

Objectives

Uterine carcinosarcoma (UCS) is an aggressive malignancy characterized by epithelial (C) and mesenchymal (S) components, with complex biology and poor treatment response. This study aims to enhance understanding of UCS through genomic, epigenomic, and transcriptomic analysis.

Methods

Microdissected (C and S) tumor samples were processed for whole-genome sequencing (WGS), RNA-seqencing, and enzymatic methylation sequencing (EM-Seq). Multiplex immunohistochemistry (mIHC) and computational pathology techniques were employed to assess tumour microenvironment (TME).

Results

WGS and EM-seq of 18 samples from 9 patients revealed a low tumor mutation burden (TMB; median = 0.97 mutations/Mb) and no evidence of microsatellite instability (MSI). Driver mutations were identified in TP53 (94 %), PIK3CA (33 %), and PPP2R1A (22 %). Copy-number (CN) analysis revealed recurrent amplifications of MYC (67 %), PIK3CA (61 %), CCNE1 (56 %), AKT2 (44 %), and SMARCA4 (39 %). Comparative analysis of the C and S regions revealed no significant differences in mutation frequency, CN, transcriptomic and methylomic profiles. Both regions exhibited global hypomethylation, with functional enrichment for xenobiotic metabolism pathways in C and epithelial-to-mesenchymal transition pathways in S regions. Comparitive mIHC performed on 21 cases showed similar T cell and B cell densities, but a higher density of tumour-associated macrophages and PD-L1+ cells in the S component. Computational morphologic analysis showed substantial histomorphologic heterogeneity within and across UCS cases.

Conclusion

By elucidating the complex interplay between the epithelial and mesenchymal components, this study enhances our understanding of UCS and informs the development of novel therapeutic strategies targeting both genomic alterations and the TME.

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.