title: Promoter hypermethylation and reduced expression of RASSF1A are frequent molecular alterations of endometrial carcinoma.
abstract: Alterations in the regulation of the RAS-MAPK pathway are frequent in endometrial carcinoma. RASSF1A is a tumor-suppressor gene that can regulate this pathway negatively. RASSF1A has been found to be inactivated by promoter methylation in some human tumors. The aim of the study was to assess the immunohistochemical expression of RASSF1A in normal endometrium and endometrial carcinoma, and to correlate its expression with K-RAS mutations, presence of microsatellite instability, RASSF1A promoter methylation, and clinicopathological data. RASSF1A immunostaining was evaluated in one tissue microarray constructed from 80 paraffin-embedded samples of normal endometrium, and two tissue microarrays constructed with a total of 157 endometrial carcinomas (one constructed with 95 endometrial carcinomas previously evaluated for K-RAS mutations, and microsatellite instability, and another one containing 62 endometrial carcinomas that were also subjected to RASSF1A promoter methylation analysis). RASSF1A immunostaining was correlated with cell proliferation (Ki67), Cyclin D1 expression and clinicopathological data. Promoter methylation of RASSF1A was assessed by methylation-specific PCR. RASSF1A immunostaining was variable during the menstrual cycle in normal endometrium. RASSF1A expression was significantly reduced in 48% of endometrial carcinomas, particularly in tumors exhibiting microsatellite instability. RASSF1A-promoter methylation was very frequent in endometrial carcinoma (74%), and was frequently associated with reduced expression of RASSF1A. RASSF1A-promoter hypermethylation was common in advanced-stage endometrial carcinoma. The results suggest that reduced expression of RASSF1A may play a role in endometrial carcinogenesis by controlling cell proliferation and apoptosis through the MAPK-signaling pathway.
authors.affiliation: Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain. jpallares@arnau.scs.es
authors.forename: Judit
authors.initials: J
authors.lastname: Pallarés
authors.forename: Ana
authors.initials: A
authors.lastname: Velasco
authors.forename: Nuria
authors.initials: N
authors.lastname: Eritja
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.forename: Miriam
authors.initials: M
authors.lastname: Cuatrecasas
authors.forename: Victor
authors.initials: V
authors.lastname: Palomar-Asenjo
authors.forename: Lluis
authors.initials: L
authors.lastname: Catasús
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
mesh_terms: D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D020929:Mitogen-Activated Protein Kinase Kinases