SG-02 * ROLE OF mTOR SIGNALLING PATHWAY IN THE PATHOGENESIS OF SUBEPENDYMAL GIANT CELL ASTROCYTOMAS

Abstract

BACKGROUND: Subependymal giant cell astrocytomas (SEGA) are slow-growing benign intraventricular tumors whose pathogenesis is debated. Recent studies have shown that TSC1 and TSC2 genes are linked to the mTOR cell signalling pathway. OBJECTIVE: We aimed to analyze TSC1 and TSC2 gene mutation, protein expression of hamartin and tuberin, and protein expression of mTOR signalling cascade in a series of SEGA to determine their role in pathogenesis. METHODS: A total of 28 cases of SEGA were retrieved from archival material. Immunohistochemistry was performed on formalin fixed, paraffin-embedded tissue using antibodies against tuberin, hamartin, phospho-p70S6kinase, S6 ribosomal, phospho-S6 ribosomal, phospho-4E-BP1, Stat 3 and phospho-Stat 3. Mutation analysis of TSC1 (exons 15 and 17) and TSC2 (exons 33, 39 and 40) was done by DNA sequencing. RESULTS: Loss of immunoexpression of either hamartin or tuberin was found in 19 cases (68%). Pathogenic point mutations in selected exons of TSC1 and TSC2 genes were present in 5 out of the 20 cases studied. Robust expression of mTOR downstream signalling molecules phospho-p70S6 Kinase (100%), S6 ribosomal (82%), phospho-S6 ribosomal (64%), phospho-4E-BP1 (64%) and Stat3 (100%) was seen. Four cases (14%) showed immunopositivity for phospho-stat3. There was no significant correlation of immunoexpression of mTOR pathway proteins with immunoloss of tuberin and hamartin. CONCLUSION: There is a definite role for TSC1 and TSC2 genes in the pathogenesis of SEGAs as evidenced by loss of protein expression and presence of pathogenic mutations. Strong expression of mTOR downstream signalling proteins indicates activation of mTOR pathway in SEGA, indicating a role for this pathway in their pathogenesis. However, how mTOR activation is linked to loss of function of TSC genes needs further elucidation.