title: Significance of PTEN alterations in endometrial carcinoma: a population-based study of mutations, promoter methylation and PTEN protein expression.
abstract: Mutations in the PTEN gene are frequent in endometrial carcinoma. PTEN methylation is an alternative mechanism of gene inactivation. To elucidate different mechanisms of PTEN gene inactivation, we have studied a population-based series of endometrial carcinomas for PTEN mutations in relation to clinicopathologic characteristics, promoter methylation and protein expression. PTEN mutations were found in 54%, mainly in exons 5 and 8; with at least two different mutations in 21%. Presence of PTEN mutation was significantly correlated with young age, low FIGO-stage, endometrioid subtype, low grade, microsatellite instability and favourable prognosis. Previous studies of these tumours have observed PTEN methylation in 18% and low protein expression in 20%. Low expression of PTEN-antibody 6H2.1 was correlated with the presence of mutations in exon 8 among patients with 'two hits'; i.e. > or =2 mutations, or mutation(s) plus methylation (p=0.001). Number of PTEN hits was significantly associated with microsatellite instability, low hMLH1 expression and hMLH1 methylation. Thus, PTEN mutations are frequent in sporadic endometrial carcinoma and define a prognostically favourable subgroup, whereas the relationship with PTEN protein expression is complex. A pathway in endometrial carcinogenesis involving PTEN mutation and microsatellite instability is confirmed, and this study also indicates the importance of PTEN and hMLH1 methylation in this pathway.
authors.affiliation: Department of Gynaecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. helga.salvesen@uib.no
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Ingunn
authors.initials: I
authors.lastname: Stefansson
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Kretzschmar
authors.forename: Paula
authors.initials: P
authors.lastname: Gruber
authors.forename: Nicola D
authors.initials: ND
authors.lastname: MacDonald
authors.forename: Andy
authors.initials: A
authors.lastname: Ryan
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Soma
authors.initials: S
authors.lastname: Das
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human