Molecular Alteration Implicated in Malignant Transformation of Peripheral Nerve Sheath Tumors (PNST): A Window to New Therapeutic Approaches.
Cleofe Romagosa, Cesar Serrano, Sara Simonetti, Javier Hernandez-Losa, Silvia Baguer, Ruth Orellana, Teresa Moline, Rosa Somoza, Santiago Ramon y Cajal. Hospital Vall d'Hebron, Barcelona, Spain; Hospital de Sant Pau, Barcelona, Spain; Hospital Parc Taulí, Sabadell, Spain
Background: Benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumors are found to be either sporadic or related to neurofibromatosis (NF). Ras-Raf-MAPK pathway activation has already been described in both groups. While NF1 and NF2 loss of function leads to oncogenic Ras signalling in NF associated tumors, other mechanisms in the sporadic setting remain unknown. Somatic BRAF mutations are involved in the pathogenesis of a wide variety of cancers by triggering the Ras-Raf-MAPK pathway, which in turn constitutes a target for new treatments. However, activation of the Ras-Raf-MAPK cascade has been also described in benign tumors, indicating that these are initial events in tumoral transformation. P16 and PTEN downregulation have been described as critical events in malignant transformation in other tumours initiated by activation of the Ras-Raf-MAPK pathway. The aim of this study was to investigate the implication of BRAF V600E mutations and P16 or PTEN downregulation in sporadic and NF-associated nerve sheath tumors.
Design: BRAF exon 15 PCR amplification and sequencing was done in 18 schwannomas (1 NF, 16 sporadic and 1 unknown), 16 neurofibromas (5 NF and 9 sporadic) and 19 MPNST (9 NF, 8 sporadic and 2=unknown). cDNA was obtained from formalin-fixed and paraffin-embedded tissue in all cases. Moreover, immunohistochemical staining was done in all the cases for p16 (V-Kit CINtec, MTM), and for PTEN (Anti-hu PTEN (6h2.1), Cascade) in a subgroup of 12 Schwannomas, 12 Neurofibromas and 17 MPNST.
Results: BRAF V600E mutations were detected in 3/16 (18.8%) sporadic schwannomas and 1/ 8 (12.5%) sporadic MPNST. No BRAF mutation were observed in any neurofibroma or any NF associated lesion. PTEN loss was observed in 5/17 (29.5%) of MPNST and 0/24 (0%) BPNST. Differences in p16 expression were observed between MPNST (8.95+/-16.78) and BPNST (45.43+/-27.77) (p=0.0001).
Conclusions: Our findings confirm the presence of BRAF V600E mutations in sporadic Schwannomas and MPNST but not in Neurofibromas. These data suggest that BRAF V600E mutation might arise as a key event in cell growth and development of a subgroup of BPNST and MPNST non-related to NF. Moreover, our data support the hypothesis that p16 and PTEN loss are critical events in malignant transformation of MPNST. Together, our results open new avenues to test and develop upcoming treatments for these group of tumors
Category: Bone & Soft Tissue
Monday, February 28, 2011 1:00 PM
Poster Session II # 14, Monday Afternoon