Malignant Peripheral Nerve Sheath Tumor Development Is Associated with PTEN Loss and Activation of the PI3K/AKT/mTOR Pathway
Maria E Vergara-Lluri, Elizabeth Shurell, Yunfeng Li, Hong Wu, Fritz C Eilber, Sarah M Dry. David Geffen School of Medicine at UCLA, Los Angeles, CA
Background: Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant inherited disorders (incidence 1:2,500) and typically causes benign peripheral neurofibromas (NF). In comparison to the general population, NF patients have a 100-fold lifetime risk of developing malignant peripheral nerve sheath tumors (MPNST). The signaling pathways that underlie the pathogenesis of NF development and malignant transformation are poorly understood. In a previous study, we demonstrated the importance of the PTEN (phosphatase and tensin homologue) tumor suppressor gene as a negative regulator of PI3K/AKT/mTOR pathway in the pathogenesis. Specifically, the loss of expression of PTEN, in combination with K-RAS activation in our mouse model, led to development of NFs with 100% penetrance, followed by MPNST transformation. The purpose of this study was to assess PTEN expression and activation of the PI3K/Akt/mTOR pathway by immunohistochemistry (IHC) in human PNSTs.
Design: PTEN and p-S6 IHC was performed on a peripheral nerve sheath tumor tissue microarray (TMA) containing 42 MPNST cases (35 primary tumors, 4 recurrent, and 3 metastatic), including both spontaneous (n=25) and NF1-associated (n=17) cases. The TMA contains triplicate cores from each case. PTEN (cytoplasmic) and p-S6 (nuclear) staining of tumor cells was scored according to cellular density: 0 staining, <1% of tumor cells; 1+ staining 1-25%; 2+ staining 26-75%; and 3+ staining >75%.
Results: Loss of PTEN expression (less than 1+) was seen in 12/25 (60%) of spontaneous and 8/17 (47%) NF-1 associated MPNSTs. A concomitant upregulation of p-S6 positivity also was seen in 10/12 (83%) spontaneous and 4/8 (50%) NF-1 associated MPNSTs.
Conclusions: PTEN loss occurs frequently in human MPNSTs and correlates with changes in the PI3K/Akt/mTOR pathway, as seen by increased expression of p-S6. This data confirms our prior studies and suggests therapeutic inhibition of this pathway may be useful in both spontaneous and NF1-associated MPNSTs.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 21, Tuesday Afternoon