PTEN Association with mTOR Pathway Activation and Outcomes in Bladder Cancer.
Mohammed Orloff, Paul Elson, Yirin Yang, Charis Eng, Donna E Hansel. Cleveland Clinic, OH
Background: We have recently identified increased mTOR pathway activation in urothelial carcinoma of the bladder (UCC). We next sought to determine the relationship of PTEN, an upstream negative mediator of the mTOR pathway, to mTOR activity and outcomes in UCC patients.
Design: Patients with UCC (n=118) were examined for PTEN expression, including intensity of expression (0 no expression, 1+ low, 2+ moderate, 3+ intense expression) and predominant subcellular localization (nuclear, non-nuclear). Results were correlated with the presence of lymph node (LN) metastases, recurrence-free survival (RFS) and overall survival by univariate and multivariate analysis. PTEN intron/exon mutational analysis was performed by denaturing gradient gel electrophoresis (DGGE) and mutational status was correlated with PTEN protein expression in a subset of 91 specimens.
Results: The majority of patients (91/118; 81%) demonstrated moderate to intense expression of PTEN, with PTEN loss in only 2 patients. PTEN was primarily localized to the nucleus in 30/116 (26%) patients, with some level of nuclear PTEN staining in 74/116 (64%) of patients. In LN metastases, reduced PTEN intensity was associated with an increased percentage of phospho-mTOR cells (p=0.02). PTEN mutational analysis identified 3 variants (c.132C>T, c.511C>G, c.892C>G) which were associated with absent PTEN protein expression and diffuse phospho-mTOR expression. Reduced RFS was correlated with positive surgical margins (p=0.09), carcinoma in situ (p=0.09) and nuclear PTEN (p=0.08). Reduced overall survival was significantly associated with metastases (p=0.04) and nuclear PTEN expression (p=0.04). Stepwise multivariable analysis showed an association between reduced RFS and LN metastases (p=0.03), carcinoma in situ (0.05) and nuclear PTEN (p=0.07).
Conclusions: Alterations in PTEN expression and subcellular localization appear to mediate mTOR pathway activity in bladder cancer cells, although few mutations appear to account for reduced PTEN expression. Nuclear localization of PTEN is a relatively new finding and its function in mediating cancer behavior is under investigation. Our finding of worsened outcomes with nuclear PTEN localization warrant further functional investigation.
Tuesday, March 1, 2011 1:30 PM
Platform Session: Section H, Tuesday Afternoon