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


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.


CONCLUSIONS
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.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Kalpana
K
Kumari
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Mehar C
MC
Sharma
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Aanchal
A
Kakkar
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Prit B
PB
Malgulwar
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Pankaj
P
Pathak
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Vaishali
V
Suri
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Chitra
C
Sarkar
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Sarat P
SP
Chandra
Institute of Genomics and Integrative Biology-Council of Scientific and Industrial Research, New Delhi, India.
Mohammed
M
Faruq
Department of Pathology, GB Pant Hospital, New Delhi, India.
Rakesh K
RK
Gupta
Department of Pathology, GB Pant Hospital, New Delhi, India.
Ravindra K
RK
Saran
D048868:Adaptor Proteins, Signal Transducing; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis; D006801:Humans; D007150:Immunohistochemistry; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D014402:Tuberous Sclerosis; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases