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

Research output: Contribution to journalArticle

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 vs. 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.

Original languageEnglish (US)
Pages (from-to)13-21
Number of pages9
JournalInternational Journal of Clinical and Experimental Pathology
Volume4
Issue number1
StatePublished - 2011

Fingerprint

Neurofibromatosis 1
Astrocytoma
S 6
Electron Microscopy
Western Blotting
70-kDa Ribosomal Protein S6 Kinases
Gene Expression

Keywords

  • Astrocytoma
  • Glioma
  • Glioneuronal
  • mTOR
  • Neurofibromatosis
  • Pilocytic astrocytoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

Cite this

Phenotypic variations in NF1-associated low grade astrocytomas : Possible role for increased mTOR activation in a subset. / Jentoft, Mark; Giannini, Caterina; Cen, Ling; Scheithauer, Bernd W.; Hoesley, Bridget; Sarkaria, Jann N; Abell-Aleff, Patrice C.; Rodriguez, Erika F.; Li, Ying; Rodriguez, Fausto J.

In: International Journal of Clinical and Experimental Pathology, Vol. 4, No. 1, 2011, p. 13-21.

Research output: Contribution to journalArticle

Jentoft, M, Giannini, C, Cen, L, Scheithauer, BW, Hoesley, B, Sarkaria, JN, Abell-Aleff, PC, Rodriguez, EF, Li, Y & Rodriguez, FJ 2011, 'Phenotypic variations in NF1-associated low grade astrocytomas: Possible role for increased mTOR activation in a subset', International Journal of Clinical and Experimental Pathology, vol. 4, no. 1, pp. 13-21.
Jentoft, Mark ; Giannini, Caterina ; Cen, Ling ; Scheithauer, Bernd W. ; Hoesley, Bridget ; Sarkaria, Jann N ; Abell-Aleff, Patrice C. ; Rodriguez, Erika F. ; Li, Ying ; Rodriguez, Fausto J. / Phenotypic variations in NF1-associated low grade astrocytomas : Possible role for increased mTOR activation in a subset. In: International Journal of Clinical and Experimental Pathology. 2011 ; Vol. 4, No. 1. pp. 13-21.
@article{834216758c1f4fd8b386a567f9d4fcf4,
title = "Phenotypic variations in NF1-associated low grade astrocytomas: Possible role for increased mTOR activation in a subset",
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 vs. 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.",
keywords = "Astrocytoma, Glioma, Glioneuronal, mTOR, Neurofibromatosis, Pilocytic astrocytoma",
author = "Mark Jentoft and Caterina Giannini and Ling Cen and Scheithauer, {Bernd W.} and Bridget Hoesley and Sarkaria, {Jann N} and Abell-Aleff, {Patrice C.} and Rodriguez, {Erika F.} and Ying Li and Rodriguez, {Fausto J.}",
year = "2011",
language = "English (US)",
volume = "4",
pages = "13--21",
journal = "International Journal of Clinical and Experimental Pathology",
issn = "1936-2625",
publisher = "e-Century Publishing Corporation",
number = "1",

}

TY - JOUR

T1 - Phenotypic variations in NF1-associated low grade astrocytomas

T2 - Possible role for increased mTOR activation in a subset

AU - Jentoft, Mark

AU - Giannini, Caterina

AU - Cen, Ling

AU - Scheithauer, Bernd W.

AU - Hoesley, Bridget

AU - Sarkaria, Jann N

AU - Abell-Aleff, Patrice C.

AU - Rodriguez, Erika F.

AU - Li, Ying

AU - Rodriguez, Fausto J.

PY - 2011

Y1 - 2011

N2 - 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 vs. 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.

AB - 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 vs. 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.

KW - Astrocytoma

KW - Glioma

KW - Glioneuronal

KW - mTOR

KW - Neurofibromatosis

KW - Pilocytic astrocytoma

UR - http://www.scopus.com/inward/record.url?scp=85021267256&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021267256&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:85021267256

VL - 4

SP - 13

EP - 21

JO - International Journal of Clinical and Experimental Pathology

JF - International Journal of Clinical and Experimental Pathology

SN - 1936-2625

IS - 1

ER -