Coscia Fabian, Nielsen Annelaura B, Weigert Melanie, Watters Karen, Javellana Melissa, Anglesio Michael, Yamada S Diane, Lastra Ricardo R, Mann Matthias, Lengyel Ernst
Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
Clin Cancer Res. 2025 Jun 3;31(11):2230-2240. doi: 10.1158/1078-0432.CCR-24-1763.
Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histologic markers to distinguish SEOCs from single-site tumors.
We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, and Tübingen). For direct comparison with single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrioid endometrial cancer (EEC). For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry-based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes.
DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors.
The integrated proteogenomic data show that SEOCs are distinguishable from endometrioid endometrial or endometrioid ovarian cancer. Based on their proteogenomic similarity to EECs, we conclude that most SEOCs represent primary EECs that have metastasized to the ovary.
越来越多基于基因组学的证据表明，同步性子宫内膜癌和卵巢癌（SEOC）代表克隆相关的原发性和转移性肿瘤。此前缺乏对SEOC全球蛋白质组格局的系统分析，这可能揭示已知基因改变的功能和疾病特异性后果、转移的方向性，以及区分SEOC与单部位肿瘤的准确组织学标志物。
我们在三个国际妇科肿瘤治疗中心（芝加哥、温哥华和图宾根）对29例诊断为SEOC的患者进行了系统的蛋白质基因组分析。为了与单部位肿瘤进行直接比较，我们纳入了9例单部位子宫内膜样卵巢癌患者和26例单部位子宫内膜样子宫内膜癌（EEC）患者。对所有64例患者，我们进行了一个275个基因的癌症检测板测序，并结合基于连续组织切片的区室分辨质谱蛋白质组学，以比较整体（6000多种蛋白质）、肿瘤和基质蛋白质组。
基于DNA的检测板测序证实，大多数SEOC是克隆相关的。整体蛋白质组分析揭示了SEOC与单部位肿瘤之间的显著差异，并强调了基质蛋白质组在定义和识别SEOC中的重要性。我们鉴定出分子独特的SEOC基质蛋白质组，其在整体上与单部位子宫内膜癌更相关。我们最终得出了一个蛋白质组学预测指标，可区分SEOC与单部位卵巢和子宫肿瘤。
整合的蛋白质基因组数据表明，SEOC可与子宫内膜样子宫内膜癌或子宫内膜样卵巢癌区分开来。基于它们与EEC的蛋白质基因组相似性，我们得出结论，大多数SEOC代表已转移至卵巢的原发性EEC。
