Sengal Asmerom T, Patch Ann-Marie, Snell Cameron E, Smith Deborah S, Leung Samuel C Y, Talhouk Aline, Williams Elizabeth D, McAlpine Jessica N, Pollock Pamela M
Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, located at the Translational Research Institute, PA Hospital Campus, 37 Kent St Woolloongabba, Brisbane, Queensland, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Clin Cancer Res. 2020 Sep 1;26(17):4569-4580. doi: 10.1158/1078-0432.CCR-19-4088. Epub 2020 May 15.
The two most common molecular subtypes of endometrial cancers, mismatch repair deficient (MMRd) and p53 wild-type (p53wt) comprise the majority of endometrial cancers and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of FGFR2 from FGFR2b to FGFR2c (normally expressed in mesenchymal cells), has been reported in other solid carcinomas. The objective of this study was to investigate the role of FGFR2c in risk stratification of endometrial cancer.
We have developed and optimized a BaseScope RNA ISH assay to detect FGFR2c. FGFR2c expression was determined in a preliminary screening cohort of 78 endometrial cancers and a clinically and molecularly annotated Vancouver cohort ( = 465). Cox regression model analyses were performed to assess the prognostic value of FGFR2c.
Univariate and multivariate analyses revealed FGFR2c expression was significantly associated with shorter disease-specific survival (DSS) and progression-free survival (PFS) in endometrioid endometrial cancer (EEC, = 302). Notably, FGFR2c expression was significantly associated with shorter PFS and DSS in patients with grade 3 EECs ( < 0.003 and < 0.002) and the European Society Medical Oncology (ESMO) high-risk group ( < 0.0001 and < 0.002), respectively. Moreover, within the MMRd subtype, FGFR2c expression was significantly associated with shorter PFS ( < 0.048) and DSS ( < 0.001).
FGFR2c expression appears an independent prognostic biomarker in patients with EEC and further discerns the outcomes within grade 3 tumors, ESMO high-risk groups, as well as within the MMRd and p53wt subtypes. FGFR2c inclusion into future molecular subtyping can further refine risk stratification of EEC.
子宫内膜癌最常见的两种分子亚型，错配修复缺陷（MMRd）和p53野生型（p53wt），占子宫内膜癌的大多数，其预后中等，需要额外的风险分层生物标志物。在其他实体癌中已报道FGFR2从FGFR2b到FGFR2c（通常在间充质细胞中表达）的异构体转换。本研究的目的是探讨FGFR2c在子宫内膜癌风险分层中的作用。
我们开发并优化了一种BaseScope RNA原位杂交检测法来检测FGFR2c。在78例子宫内膜癌的初步筛查队列和一个经过临床和分子注释的温哥华队列（n = 465）中测定FGFR2c表达。进行Cox回归模型分析以评估FGFR2c的预后价值。
单变量和多变量分析显示，在子宫内膜样腺癌（EEC，n = 302）中，FGFR2c表达与较短的疾病特异性生存期（DSS）和无进展生存期（PFS）显著相关。值得注意的是，在3级EEC患者中，FGFR2c表达分别与较短的PFS和DSS显著相关（P < 0.003和P < 0.002），以及与欧洲医学肿瘤学会（ESMO）高危组（P < 0.0001和P < 0.002）显著相关。此外，在MMRd亚型中，FGFR2c表达与较短的PFS（P < 0.048）和DSS（P < 0.001）显著相关。
FGFR2c表达似乎是EEC患者的一个独立预后生物标志物，并进一步区分3级肿瘤、ESMO高危组以及MMRd和p53wt亚型内的预后。将FGFR2c纳入未来的分子分型可以进一步优化EEC的风险分层。
