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 NI FEATURE: PATHOLOGICAL PANORAMA - ORIGINAL ARTICLE
Year : 2016  |  Volume : 64  |  Issue : 5  |  Page : 988--994

Role of mTOR signaling pathway in the pathogenesis of subependymal giant cell astrocytoma – A study of 28 cases


1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
3 Institute of Genomics and Integrative Biology–Council of Scientific and Industrial Research, New Delhi, India
4 Department of Pathology, GB Pant Hospital, New Delhi, India

Correspondence Address:
Mehar C Sharma
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.190274

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Background: Subependymal giant cell astrocytomas (SEGA) are slow-growing benign intraventricular tumors, the pathogenesis of which is debated. Recent studies have shown that tuberous sclerosis complex (TSC) 1 and TSC2 genes are linked to the mammalian target of rapamycin (mTOR) cell signaling pathway. We aimed to analyze TSC1 and TSC2 gene mutation, hamartin and tuberin protein expression, and protein expression of mTOR signaling cascade in a series of SEGA to determine their role in pathogenesis. Materials and Methods: Twenty-eight SEGA cases were retrieved from archival material. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue using antibodies against tuberin, hamartin, phospho-p70S6 kinase, S6 ribosomal protein, phospho-S6 ribosomal protein, phospho-4E-BP1, Stat3, and phospho-Stat3. 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 of 20 cases studied. Robust expression of mTOR downstream signaling molecules phospho-p70S6 kinase (100%), S6 ribosomal protein (82%), phospho-S6 ribosomal protein (64%), phospho-4E-BP1 (64%), and Stat3 (100%) was seen. Four cases (14%) showed immunopositivity for phospho-Stat3. There was no significant correlation of these markers with immunoloss of tuberin and hamartin. Significance: There is a definite role for TSC1 and TSC2 genes in the pathogenesis of SEGA as evidenced by loss of protein expression and presence of mutations. Strong expression of mTOR downstream signaling proteins indicates activation of mTOR pathway in these tumors, suggesting that proteins in this pathway may have the potential to serve as therapeutic targets in these patients.






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