Abstracts Category : Other

Study of related senescence pathways in soft tissue tumors development

by Sara Simonetti

Introduction: In this thesis we have studied and analyzed markers of cellular senescence in a subset of soft tissue tumors, peripheral nerve sheath tumors (PNSTs), neoplasms that may occur sporadically or be associated with clinical syndromes such as neurofibromatosis (NFs).Oncogenic-induced senescence (OIS) is a growth-arrest mechanism demonstrated in cells and in some type of human cancers. For this reason it is considered a tumor suppressor process against malignant transformation. Different molecular pathways are involved in this process, such as RAS/RAF/MAPK or ARF/p53 and p16INK4a/pRb.Among the PNSTs, schwannomas represent a subset of benign tumors that only very rarely undergo malignant changes. These tumors, like nevus, are composed of cells derived from the neural crest. While in the nevus is clear that the main mechanism preventing malignant transformation is the entry into senescence, in response to activation of the RAS/MAPK/RAF pathway (BRAF mutation V600E), the mechanisms involved in the development of PNSTs remain still unknown.The PNSTs occurring in NFs are related to alterations in two specific genes of these syndromes, NF1 and NF2, able to activate the RAS/MAPK/RAF pathway. However, very little is known about the pathogenesis of sporadic PNSTs and malignant transformation of schwannomas.This study analyzes the markers of senescence in PNSTs, in order to demonstrate the potential role of senescence in their tumorigenesis, along with the presence or absence of BRAF V600E mutations in these tumors, especially in sporadic ones.Methods: A retrospective immunohistochemical study was done in 39 schwannomas and 18 malignant peripheral nerve sheath tumors (MPNSTs). Staining for p16INK4a, Ki67, p53 and Cyclin D1 was performed in all the cases. Additionally, SA--Gal staining was done in those cases in which frozen tissue was available (n=8). Moreover BRAF exon 15 and KRAS exons 2 and 3 polymerase chain reaction (PCR) sequencing was performed in formalin-fixed/paraffin-embedded samples of 59 schwannomas, 16 neurofibromas and 24 MPNSTs, related and non-related to NF types 1 and 2. Results: In schwannomas we found high expression of p16INK4a, low or absent levels of Ki67 and positivity of SA--Gal activity. An opposite pattern was found in MPNSTs. Oncogenic BRAF V600E mutations were observed in 4/40 schwannomas and 1/13 MPNST, not associated with NF. A KRAS G12S mutation was also evident in one sporadic schwannoma.Conclusions: Our results support the senescence nature of schwannomas and the absence of senescence phenotype in MPNSTs. Moreover the finding of BRAF V600E and KRAS mutations in a subset of PNSTs not related to NF represents an important event especially for the development of novel specific treatment for these tumors.Advisors/Committee Members: [emailprotected] (authoremail), true (authoremailshow), Ramn y Cajal Agueras, Santiago (director), Romagosa Prez-Portabella, Cleof (director), true (authorsendemail).