Background: Endometrioid and serous carcinomas of the uterus, the two most common histological types of endometrial carcinoma, have been shown to have distinct clinicopathological characteristics and to be underpinned by distinct constellations of molecular aberrations. We sought to define the biological processes that govern the clinical behavior of endometrial cancers based on their transcriptomic characteristics as defined by RNA-sequencing.

Material and Methods: RNA-sequencing-based gene expression and clinicopathological data from 323 endometrial cancers were retrieved from The Cancer Genome Atlas (TCGA). Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. TCGA RNA-sequencing data were used to determine the transcription module of each prototype gene. The expression of prototype genes and modules and their association with outcome was assessed in univariate and multivariate survival models in the whole cohort, and in specific subtypes, including endometrioid vs serous, grade 1, 2 and 3 cancers, and the genomic subtypes as described in the TCGA study.

Results: The clinical behavior of endometrial cancers was found to be associated with hormone receptor signaling, PI3K pathway signaling and DNA mismatch repair processes. Furthermore, when adjusted for the known prognostic clinicopathological parameters, we found that MSH6 mRNA expression was independently associated with the outcome of patients with endometrial cancer. At variance with other hormone-driven tumors, such as breast cancer, the level of expression of proliferation-related genes was not a predictor of outcome in patients with endometrial cancers. The biological processes governing the outcome of endometrioid and serous endometrial cancers were shown to be distinct; whilst in endometrioid carcinomas hormone receptor, PI3K and DNA mismatch repair modules were associated significantly with outcome in univariate analysis, the clinical behavior of serous cancers was significantly associated with the expression of the apoptosis-related gene CASP3 and Wnt signaling (CTNNB1). When stratified according to grade, the PLAU prototype gene and its invasion module were found to be significantly associated with the survival of patients with grade 3 endometrial cancer, but not of those with grade 1 or 2 cancers.

Conclusion: Our data suggest that stratification of endometrial cancers according to histological type (i.e. endometrioid vs serous) and potentially grade may be of importance for the design of clinical trials testing targeted therapeutics as these parameters define subgroups of endometrial cancers that not only have distinct genetic aberrations but also distinct molecular pathways that define the outcome of patients with this disease.

Citation Format: Britta Weigelt, Christophe Lemetre, Charlotte K.Y. Ng, Salvatore Piscuoglio, Jorge S. Reis-Filho. The clinical behavior of endometrioid and serous endometrial carcinomas is governed by distinct biological processes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1544. doi:10.1158/1538-7445.AM2014-1544