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Reduced TSC2 RNA and protein in sporadic astrocytomas and ependymomas
R Wienecke1, A Guha, J C Maize
1Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD, USA.
Abstract:
Individuals affected with tuberous sclerosis complex (TSC) develop several benign and malignant tumors at increased frequency, including astrocytomas. Tuberin, the protein product of the tuberous sclerosis complex-2 (TSC2) tumor suppressor gene, has been shown to directly inhibit cell growth and is expressed at high levels in normal central nervous system neurons and astrocytes. To determine whether TSC2 RNA and protein are reduced in astrocytomas from individuals without tuberous sclerosis, reverse transcriptase-polymerase chain reaction and immunoblotting analyses were performed on 49 adult astrocytomas, 10 pediatric astrocytomas, and 13 ependymomas. Eighteen of 40 (45%) high-grade (World Health Organization [WHO] grade III/IV) astrocytomas and 4 of 8 (50%) adult low-grade (WHO grade II) astrocytomas demonstrated reduced or absent TSC2 expression, including 1 giant cell astrocytoma, whereas none of the 10 pediatric low-grade astrocytomas analyzed showed a reduction in TSC2 expression. Reduced or absent tuberin was observed in 2 of 6 (33%) ependymomas analyzed. These data demonstrate, for the first time, that reduced or absent TSC2 expression may represent one of the critical genetic events associated with the development of sporadic adult, but not pediatric, astrocytomas.
Insights
Reduced tuberous sclerosis complex-2 (TSC2) gene expression is linked to adult astrocytomas, but not pediatric ones. This finding suggests TSC2 loss is a key event in sporadic adult astrocytoma development.
Area of Science:
- Neuro-oncology
- Cancer Genetics
- Molecular Biology
Background:
- Tuberous sclerosis complex (TSC) predisposes individuals to tumors, including astrocytomas.
- The TSC2 gene product, tuberin, inhibits cell growth and is vital in the central nervous system.
- Astrocytomas are common brain tumors, and their genetic underpinnings are actively researched.
Purpose of the Study:
- To investigate TSC2 RNA and protein expression in astrocytomas from individuals without TSC.
- To determine if reduced TSC2 expression is associated with adult versus pediatric astrocytomas.
- To explore the role of TSC2 in the pathogenesis of sporadic astrocytomas.
Main Methods:
- Reverse transcriptase-polymerase chain reaction (RT-PCR) to assess TSC2 RNA levels.
- Immunoblotting to quantify TSC2 protein expression.
- Analysis of 49 adult astrocytomas, 10 pediatric astrocytomas, and 13 ependymomas.
Main Results:
- Reduced or absent TSC2 expression was found in 45% of high-grade and 50% of adult low-grade astrocytomas.
- No TSC2 reduction was observed in pediatric low-grade astrocytomas.
- TSC2 downregulation was also noted in 33% of analyzed ependymomas.
Conclusions:
- Reduced or absent TSC2 expression is associated with sporadic adult astrocytomas.
- This genetic alteration appears critical in the development of adult, but not pediatric, astrocytomas.
- TSC2 loss may be an early event in the tumorigenesis of adult astrocytomas.