Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway.
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
Gynecol Oncol. 2014 Sep;134(3):599-606. doi: 10.1016/j.ygyno.2014.06.026. Epub 2014 Jul 1.
Our previously reported 29-gene expression signature identified an aggressive subgroup of endometrial cancer patients with PI3K activation. We here wanted to validate these findings by independent patient series.
The 29-gene expression signature was assessed in fresh frozen tumor tissue from 280 primary endometrial carcinomas (three independent cohorts), 19 metastatic lesions and in 333 primary endometrial carcinomas using TCGA data, and expression was related to clinico-pathologic features and survival. The 29-gene signature was assessed by real-time quantitative PCR, DNA oligonucleotide microarrays, or RNA sequencing. PI3K alterations were assessed by immunohistochemistry, DNA microarrays, DNA sequencing, SNP arrays or fluorescence in situ hybridization. A panel of markers of epithelial-mesenchymal transition (EMT) was also correlated to the 29-gene signature score.
High 29-gene Endometrial Carcinoma Recurrence Score (ECARS) values consistently validated to identify patients with aggressive clinico-pathologic phenotype and reduced survival. Within the presumed favorable subgroups of low grade, endometrioid tumors confined to the uterus, high ECARS still predicted a poor prognosis. The score was higher in metastatic compared to primary lesions (P<0.001) and was significantly associated with potential measures of PI3K activation, markers of EMT and vascular invasion as an indicator of metastatic spread (all P<0.001).
ECARS validates to identify aggressive endometrial carcinomas in multiple, independent patients cohorts. The higher signature score in metastatic compared to primary lesions, and the potential link to PI3K activation and EMT, support further studies of ECARS in relation to response to PI3K and EMT inhibitors in clinical trials of metastatic endometrial carcinoma.
我们之前报道的 29 基因表达谱鉴定了具有 PI3K 激活的子宫内膜癌患者的侵袭性亚群。我们希望通过独立的患者系列来验证这些发现。
在 280 例原发性子宫内膜癌（三个独立队列）、19 例转移病灶和 333 例原发性子宫内膜癌的新鲜冷冻肿瘤组织中评估 29 基因表达谱，使用 TCGA 数据将表达与临床病理特征和生存相关联。通过实时定量 PCR、DNA 寡核苷酸微阵列或 RNA 测序评估 29 基因谱。通过免疫组化、DNA 微阵列、DNA 测序、SNP 阵列或荧光原位杂交评估 PI3K 改变。还将上皮-间充质转化（EMT）的标志物与 29 基因谱评分相关联。
高 29 基因子宫内膜癌复发评分（ECARS）值一致地鉴定出具有侵袭性临床病理表型和降低生存的患者。在低级别、局限于子宫的子宫内膜样肿瘤的假定有利亚组中，高 ECARS 仍然预测预后不良。与原发性病变相比，转移性病变中的 ECARS 更高（P<0.001），并且与潜在的 PI3K 激活措施、EMT 标志物和作为转移扩散指标的血管侵犯显著相关（均 P<0.001）。
ECARS 可验证用于在多个独立的患者队列中鉴定侵袭性子宫内膜癌。与原发性病变相比，转移性病变中的签名评分更高，以及与 PI3K 激活和 EMT 的潜在联系，支持进一步研究 ECARS 与临床试验中转移性子宫内膜癌对 PI3K 和 EMT 抑制剂的反应之间的关系。
