Significance of PTEN alterations in endometrial carcinoma: A population-based study of mutations, promoter methylation and PTEN protein expression

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. ≥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.