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

Abstract

Background Endometrial carcinoma comprises a group of tumors with distinct histologic and molecular features, and clinical behavior. Here we sought to define the biological processes that govern the clinical behavior 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 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 behavior of endometrial carcinomas as a group was associated with hormone receptor signaling, PI3K pathway signaling and DNA mismatch repair processes. When analyzed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behavior of serous cancers was likely governed by apoptosis and Wnt signaling. Multivariate survival analysis revealed that MSH6 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.

Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value

“…However, in the recurrent setting, reevaluation of MMR status in the operative biopsy should be considered as this may qualify for treatment with immune checkpoint inhibitor. Studies have previously suggested MSH6 as a potential prognostic marker in endometrial cancer, where high MSH6 in hysterectomy tissue is associated with poor outcome and nonendometrioid subtype [19,35]. Our data validate these findings and demonstrates a strong prognostic value in preoperative samples in this large prospective endometrial cancer cohort.…”

“…High MSH6 also yields prognostic value across other cancer types, suggesting that MSH6 may function to promote aggressive tumour behaviour [13][14][15][16][17]19]. However, the mechanism underlying overexpression of MSH6 is largely unknown.…”

“…In contrast, increased mRNA expression of PMS2 is associated with improved overall survival in ovarian cancer [ 18 ], MSH2 fails to predict progression-free survival in bladder cancer and high MSH2 predicts improved overall survival in Stage I–II colon cancer [ 16 ]. To our knowledge, only one study has explored differential MMR protein expression in relation to prognosis in endometrial cancer, where high MSH6 (RNA and protein) associated with poor disease-free survival in a cohort of 243 patients with mostly endometrioid histologies [ 19 ].…”

The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

“…In addition, Goodfellow et al, in a cohort of 1002 patients with EC, showed that the most common MMR defect was MLH1 loss followed by combined MSH2/MSH6 losses, then MSH6 loss alone at 70%, 20.5%, and 19.6%, respectively [ 71 ]. Several articles highlighted an increased prevalence of MSH6 mutations representing 3.8% (95% CI 1.0–9.5%) of patients with EC compared to 2.6% (95% CI 0.5–7.4%) of patients with HNPCC tumors [ 167 , 168 , 169 ]. It is, thus, essential to screen patients with EC with IHC using the four proteins.…”

Development and Validation of an Mesenchymal-Related Long Non-Coding RNA Prognostic Model in Glioma

“…In this work, we used bioinformatics and statistical tools to systematically analyze the prognostic accuracy of lncRNAs associated with mesenchymal subtype, similar to the construction of immune-related lncRNAs model (46). We integrated multiple MES-related lncRNAs into a single model and explored whether the model played a more important role in the prognostic evaluation of gliomas.…”