ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features

Adriana Olar, Diep Tran, Vidya P. Mehta, Annekathrin Reinhardt, Jawad H. Manekia, Maria Garnovskaya, Benjamin Ellezam, Rajyalakshmi Luthra, Erik P. Sulman, Carrie A. Mohila, Gerald Campbell, Suzanne Z. Powell, Gregory N. Fuller, Kenneth D. Aldape, Adekunle M. Adesina

Research output: Contribution to journalArticle

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Abstract

Introduction: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. Materials and methods: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. Results: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. Conclusion: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.

Original languageEnglish (US)
Pages (from-to)59-73
Number of pages15
JournalClinical Neuropathology
Volume38
Issue number2
DOIs
StatePublished - Mar 1 2019

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Astrocytoma
Phosphatidylinositol 3-Kinases
Neoplasms
Proteins
Immunohistochemistry
MAP Kinase Signaling System
Loss of Heterozygosity
Cerebellum
Necrosis
Mutation

Keywords

  • Anaplastic
  • MAPK/ERK
  • MYB-ATRX
  • PI3K/AKT
  • Pilocytic astrocytoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology

Cite this

Olar, A., Tran, D., Mehta, V. P., Reinhardt, A., Manekia, J. H., Garnovskaya, M., ... Adesina, A. M. (2019). ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features. Clinical Neuropathology, 38(2), 59-73. https://doi.org/10.5414/NP301105

ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features. / Olar, Adriana; Tran, Diep; Mehta, Vidya P.; Reinhardt, Annekathrin; Manekia, Jawad H.; Garnovskaya, Maria; Ellezam, Benjamin; Luthra, Rajyalakshmi; Sulman, Erik P.; Mohila, Carrie A.; Campbell, Gerald; Powell, Suzanne Z.; Fuller, Gregory N.; Aldape, Kenneth D.; Adesina, Adekunle M.

In: Clinical Neuropathology, Vol. 38, No. 2, 01.03.2019, p. 59-73.

Research output: Contribution to journalArticle

Olar, A, Tran, D, Mehta, VP, Reinhardt, A, Manekia, JH, Garnovskaya, M, Ellezam, B, Luthra, R, Sulman, EP, Mohila, CA, Campbell, G, Powell, SZ, Fuller, GN, Aldape, KD & Adesina, AM 2019, 'ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features', Clinical Neuropathology, vol. 38, no. 2, pp. 59-73. https://doi.org/10.5414/NP301105
Olar, Adriana ; Tran, Diep ; Mehta, Vidya P. ; Reinhardt, Annekathrin ; Manekia, Jawad H. ; Garnovskaya, Maria ; Ellezam, Benjamin ; Luthra, Rajyalakshmi ; Sulman, Erik P. ; Mohila, Carrie A. ; Campbell, Gerald ; Powell, Suzanne Z. ; Fuller, Gregory N. ; Aldape, Kenneth D. ; Adesina, Adekunle M. / ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features. In: Clinical Neuropathology. 2019 ; Vol. 38, No. 2. pp. 59-73.
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abstract = "Introduction: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. Materials and methods: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. Results: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50{\%} of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. Conclusion: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.",
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T1 - ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features

AU - Olar, Adriana

AU - Tran, Diep

AU - Mehta, Vidya P.

AU - Reinhardt, Annekathrin

AU - Manekia, Jawad H.

AU - Garnovskaya, Maria

AU - Ellezam, Benjamin

AU - Luthra, Rajyalakshmi

AU - Sulman, Erik P.

AU - Mohila, Carrie A.

AU - Campbell, Gerald

AU - Powell, Suzanne Z.

AU - Fuller, Gregory N.

AU - Aldape, Kenneth D.

AU - Adesina, Adekunle M.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Introduction: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. Materials and methods: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. Results: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. Conclusion: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.

AB - Introduction: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. Materials and methods: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. Results: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. Conclusion: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.

KW - Anaplastic

KW - MAPK/ERK

KW - MYB-ATRX

KW - PI3K/AKT

KW - Pilocytic astrocytoma

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DO - 10.5414/NP301105

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