Correlation of PTEN loss and PI3K/AKT/mTOR pathway upregulation with malignant peripheral nerve sheath tumor (MPNST) development and outcome.

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10555 Background: MPNST is an aggressive soft tissue sarcoma often arising from preexisting neurofibromas (NF). Our previous study using murine models demonstrated that PTEN loss and PI3K/AKT/mTOR pathway upregulation is a potential mechanism of malignant transformation. The goal of this study is to determine whether a similar mechanism also drives human MPNST development. Methods: A tissue microarray was created from 144 surgical specimens (MPNST n=58, NF n=51, schwannoma n=11, and normal nerve n=24). Cores were stained in triplicate for PTEN and PI3K pathway-associated markers (PTEN, P-AKT, P-S6, GLUT1, SKP-2), other previously identified alterations (p53, p16, P-ERK and c-Myc) as well as tumor grade biomarkers Ki-67 and cleaved caspase 3. Density, intensity and subcellular localization of each marker were quantified and compared using linear regression and survival analysis was performed using Cox proportional hazards modeling. Results: Consistent with our mouse model study, P-S6, GLUT1 and SKP-2, downstream surrogate markers for PI3K pathway, are upregulated in MPNST compared to benign NF (p=0.002, p=0.000, p=0.016, respectively). Upregulated GLUT1 is notable as we have shown that FDG imaging can be used to stratify MPNST lesions from benign. In the 34 primary MPNST patients, PTEN protein expression correlated with improved disease specific survival (DSS) and disease free survival (DFS) (p=0.066 and p=0.014, respectively). In this cohort, large size (p=0.085), low PTEN (p=0.066), and low c-MYC (p=0.001) were associated with poor DSS. Large size (p=0.074), low PTEN (p=0.023), skp2 (p=0.097), p-AKT (p=0.086), and c-MYC (p=0.001) all correlated with poor DFS. NF-1 patients and spontaneous patients had different expression patterns associated with survival. NF-1 patients had improved DSS with high p53 (p=0.044) and smaller size (p=0.013), whereas spontaneous patients showed improved DSS only with increased c-MYC (p=0.008). Conclusions: PTEN loss and PI3K/AKT/mTOR pathway activation are important in MPNST development/prognosis and serves as a potential therapeutic target.