RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers

BACKGROUND: Endometrial carcinoma comprises a group of tumours with distinct histologic and molecular features and clinical behaviour. Here, we sought to define the biological processes that govern the clinical behaviour of endometrial cancers. METHODS: Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers from The Cancer Genome Atlas (TCGA) 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 analyses. The association of MSH6 expression with outcome was validated in an independent cohort of 243 primary endometrial cancers using immunohistochemistry. RESULTS: We observed that the clinical behaviour of endometrial cancers as a group was associated with hormone receptor signalling, PI3K pathway signalling and DNA mismatch repair processes. When analysed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behaviour of serous cancers was likely governed by apoptosis and Wnt signalling. Multivariate survival analysis revealed that MSH6 gene expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level. CONCLUSION: Endometrioid and serous endometrial cancers are underpinned by distinct molecular pathways. MSH6 expression levels may be associated with outcome in endometrial cancers as a group.