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Int J Clin Exp Pathol 2011;4(1):43-57
Original Article
Phenotypic variations in NF1-associated low grade astrocytomas: possible role for
increased mTOR activation in a subset
Mark Jentoft, Caterina Giannini, Ling Cen, Bernd W. Scheithauer, Bridget Hoesley, Jann N. Sarkaria, Patrice C. Abell-Aleff, Erika F. Rodriguez,
Ying Li, Fausto J. Rodriguez
Departments of Laboratory Medicine and Pathology, Radiation Oncology, Advanced Genomics Technology Center, Biochemistry and Molecular
Biology, Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA; Department of Pathology, Johns Hopkins University,
Bethesda, MD, USA.
Received December 7, 2010; accepted December 11, 2010; Epub December 12, 2010; published January 1, 2011
Abstract: Low grade astrocytomas are the most common CNS tumors in neurofibromatosis type 1(NF1) patients. While most are classic
pilocytic astrocytomas (PA), some are difficult to classify, and have been termed “low grade astrocytoma subtype indeterminate” (LGSI). Some
of these tumors exhibit peculiar morphologies, including plump cytoplasmic processes and macronucleoli. In the current study we performed
electron microscopy, followed by gene expression, immunohistochemical and western blot analyses in an effort to identify biological
differences underlying phenotypic variation in NF1-associated low grade astrocytoma. Electron microscopy demonstrated intermediate
filaments and frequent Rosenthal fiber material in both PA and LGSI. Dense core granules and/or aligned microtubules were present in the
LGSI group (2 of 3 cases) and in the PA group (1 of 10 cases). Analysis of global gene expression data obtained using Affymetrix HG-U133
Plus2.0 chips (5 PA, 1 LGSI), and western blot analysis for phospho-S6 (1 LGSI, 2 PA) demonstrated a gene expression profile reflecting
“neuronal differentiation” and increased phospho-S6 immunoreactivity consistent with mTOR activation in the LGSI compared with PA. These
findings were confirmed by immunohistochemistry for neuronal markers, as well as combined phospho-S6/ phospho-p70S6K
immunoreactivity in 4 (of 4) LGSI and 5 (of 13) NF1-associated PA (p=0.02), and 13 (of 39) sporadic PA. Phospho-ERK immunoreactivity was
uniformly present in PA and LGSI groups, while BRAF duplication was absent by FISH in 8 NF1-associated low grade astrocytomas. In
summary, differential expression of neuronal-related genes and increased mTOR activation may underlie phenotypic variations in NF1-
associated low grade astrocytomas. (IJCEP1012004).
Keywords: Neurofibromatosis, glioma, astrocytoma, pilocytic astrocytoma, mTOR, glioneuronal
Full text PDF
Address all correspondence to:
Fausto J. Rodriguez, MD
Department of Pathology
Division of Neuropathology
Johns Hopkins University
720 Rutland Avenue - Ross Building - 512B
Baltimore, Maryland 21205
Phone - 443-287-6646
Fax - 410-955-9777
E-mail: frodrig4@jhmi.edu
Original Article
Phenotypic variations in NF1-associated low grade astrocytomas: possible role for
increased mTOR activation in a subset
Mark Jentoft, Caterina Giannini, Ling Cen, Bernd W. Scheithauer, Bridget Hoesley, Jann N. Sarkaria, Patrice C. Abell-Aleff, Erika F. Rodriguez,
Ying Li, Fausto J. Rodriguez
Departments of Laboratory Medicine and Pathology, Radiation Oncology, Advanced Genomics Technology Center, Biochemistry and Molecular
Biology, Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA; Department of Pathology, Johns Hopkins University,
Bethesda, MD, USA.
Received December 7, 2010; accepted December 11, 2010; Epub December 12, 2010; published January 1, 2011
Abstract: Low grade astrocytomas are the most common CNS tumors in neurofibromatosis type 1(NF1) patients. While most are classic
pilocytic astrocytomas (PA), some are difficult to classify, and have been termed “low grade astrocytoma subtype indeterminate” (LGSI). Some
of these tumors exhibit peculiar morphologies, including plump cytoplasmic processes and macronucleoli. In the current study we performed
electron microscopy, followed by gene expression, immunohistochemical and western blot analyses in an effort to identify biological
differences underlying phenotypic variation in NF1-associated low grade astrocytoma. Electron microscopy demonstrated intermediate
filaments and frequent Rosenthal fiber material in both PA and LGSI. Dense core granules and/or aligned microtubules were present in the
LGSI group (2 of 3 cases) and in the PA group (1 of 10 cases). Analysis of global gene expression data obtained using Affymetrix HG-U133
Plus2.0 chips (5 PA, 1 LGSI), and western blot analysis for phospho-S6 (1 LGSI, 2 PA) demonstrated a gene expression profile reflecting
“neuronal differentiation” and increased phospho-S6 immunoreactivity consistent with mTOR activation in the LGSI compared with PA. These
findings were confirmed by immunohistochemistry for neuronal markers, as well as combined phospho-S6/ phospho-p70S6K
immunoreactivity in 4 (of 4) LGSI and 5 (of 13) NF1-associated PA (p=0.02), and 13 (of 39) sporadic PA. Phospho-ERK immunoreactivity was
uniformly present in PA and LGSI groups, while BRAF duplication was absent by FISH in 8 NF1-associated low grade astrocytomas. In
summary, differential expression of neuronal-related genes and increased mTOR activation may underlie phenotypic variations in NF1-
associated low grade astrocytomas. (IJCEP1012004).
Keywords: Neurofibromatosis, glioma, astrocytoma, pilocytic astrocytoma, mTOR, glioneuronal
Full text PDF
Address all correspondence to:
Fausto J. Rodriguez, MD
Department of Pathology
Division of Neuropathology
Johns Hopkins University
720 Rutland Avenue - Ross Building - 512B
Baltimore, Maryland 21205
Phone - 443-287-6646
Fax - 410-955-9777
E-mail: frodrig4@jhmi.edu
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