Christophe Lemetre1, Begoña Vieites2, Charlotte K Y Ng1, Salvatore Piscuoglio1, Anne M Schultheis1, Caterina Marchiò3, Rajmohan Murali4, Maria A Lopez-García2, Jose C Palacios5, Achim A Jungbluth1, Luigi M Terracciano6, Jorge S Reis-Filho7, Britta Weigelt8. 1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Department of Pathology, University of Seville, University Hospital Virgen del Rocío, Seville, Spain. 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medical Sciences, University of Turin, Turin, Italy. 4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Department of Anatomic Pathology, University Hospital Ramón y Cajal, Madrid, Spain. 6. Molecular Pathology Division, Institute of Pathology, University Hospital Basel, Basel, Switzerland. 7. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: weigeltb@mskcc.org.
Abstract
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.
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 cancerpatients 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.
Authors: Brian D Lehmann; Joshua A Bauer; Xi Chen; Melinda E Sanders; A Bapsi Chakravarthy; Yu Shyr; Jennifer A Pietenpol Journal: J Clin Invest Date: 2011-07 Impact factor: 14.808
Authors: Judit Pallares; Elena Bussaglia; Jose Luis Martínez-Guitarte; Xavier Dolcet; David Llobet; Montserrat Rue; Lidia Sanchez-Verde; Jose Palacios; Jaime Prat; Xavier Matias-Guiu Journal: Mod Pathol Date: 2005-05 Impact factor: 7.842