Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

Fausto J. Rodriguez, Jacqueline A. Brosnan-Cashman, Sariah J. Allen, M. Adelita Vizcaino, Caterina Giannini, Sandra Camelo-Piragua, Milad Webb, Marcus Matsushita, Nitin Ramesh Wadhwani, Abeer Tabbarah, Dima Hamideh, Liqun Jiang, Liam Chen, Leonidas D. Arvanitis, Hussein H. Alnajar, John R. Barber, Alicia Rodríguez-Velasco, Brent Orr, Christopher M. Heaphy

Research output: Contribution to journalArticle

Abstract

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

Original languageEnglish (US)
Pages (from-to)126-140
Number of pages15
JournalBrain Pathology
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Telomere Homeostasis
Anaplasia
Astrocytoma
Mutation
Pediatrics
Neoplasms
Telomere
DNA Sequence Analysis
Glioma
Necrosis
Immunohistochemistry

Keywords

  • ATRX
  • H3-K27M
  • alternative lengthening of telomeres
  • glioma
  • pilocytic astrocytoma

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pathology and Forensic Medicine
  • Clinical Neurology

Cite this

Rodriguez, F. J., Brosnan-Cashman, J. A., Allen, S. J., Vizcaino, M. A., Giannini, C., Camelo-Piragua, S., ... Heaphy, C. M. (2019). Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia. Brain Pathology, 29(1), 126-140. https://doi.org/10.1111/bpa.12646
Rodriguez, Fausto J. ; Brosnan-Cashman, Jacqueline A. ; Allen, Sariah J. ; Vizcaino, M. Adelita ; Giannini, Caterina ; Camelo-Piragua, Sandra ; Webb, Milad ; Matsushita, Marcus ; Wadhwani, Nitin Ramesh ; Tabbarah, Abeer ; Hamideh, Dima ; Jiang, Liqun ; Chen, Liam ; Arvanitis, Leonidas D. ; Alnajar, Hussein H. ; Barber, John R. ; Rodríguez-Velasco, Alicia ; Orr, Brent ; Heaphy, Christopher M. / Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia. In: Brain Pathology. 2019 ; Vol. 29, No. 1. pp. 126-140.
@article{8dd911b288ee41bba18429a0acac4afc,
title = "Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia",
abstract = "Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22{\%}). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69{\%}) cases and ATRX loss in 20 (57{\%}), mostly in the expected association of ALT+/ATRX- (20/24, 83{\%}) or ALT-/ATRX+ (11/11, 100{\%}). BRAF duplication was present in 8 (of 26) (31{\%}). H3-K27M was present in 5 of 32 (16{\%}) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.",
keywords = "ATRX, H3-K27M, alternative lengthening of telomeres, glioma, pilocytic astrocytoma",
author = "Rodriguez, {Fausto J.} and Brosnan-Cashman, {Jacqueline A.} and Allen, {Sariah J.} and Vizcaino, {M. Adelita} and Caterina Giannini and Sandra Camelo-Piragua and Milad Webb and Marcus Matsushita and Wadhwani, {Nitin Ramesh} and Abeer Tabbarah and Dima Hamideh and Liqun Jiang and Liam Chen and Arvanitis, {Leonidas D.} and Alnajar, {Hussein H.} and Barber, {John R.} and Alicia Rodr{\'i}guez-Velasco and Brent Orr and Heaphy, {Christopher M.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/bpa.12646",
language = "English (US)",
volume = "29",
pages = "126--140",
journal = "Brain Pathology",
issn = "1015-6305",
publisher = "Wiley-Blackwell",
number = "1",

}

Rodriguez, FJ, Brosnan-Cashman, JA, Allen, SJ, Vizcaino, MA, Giannini, C, Camelo-Piragua, S, Webb, M, Matsushita, M, Wadhwani, NR, Tabbarah, A, Hamideh, D, Jiang, L, Chen, L, Arvanitis, LD, Alnajar, HH, Barber, JR, Rodríguez-Velasco, A, Orr, B & Heaphy, CM 2019, 'Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia' Brain Pathology, vol. 29, no. 1, pp. 126-140. https://doi.org/10.1111/bpa.12646

Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia. / Rodriguez, Fausto J.; Brosnan-Cashman, Jacqueline A.; Allen, Sariah J.; Vizcaino, M. Adelita; Giannini, Caterina; Camelo-Piragua, Sandra; Webb, Milad; Matsushita, Marcus; Wadhwani, Nitin Ramesh; Tabbarah, Abeer; Hamideh, Dima; Jiang, Liqun; Chen, Liam; Arvanitis, Leonidas D.; Alnajar, Hussein H.; Barber, John R.; Rodríguez-Velasco, Alicia; Orr, Brent; Heaphy, Christopher M.

In: Brain Pathology, Vol. 29, No. 1, 01.01.2019, p. 126-140.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

AU - Rodriguez, Fausto J.

AU - Brosnan-Cashman, Jacqueline A.

AU - Allen, Sariah J.

AU - Vizcaino, M. Adelita

AU - Giannini, Caterina

AU - Camelo-Piragua, Sandra

AU - Webb, Milad

AU - Matsushita, Marcus

AU - Wadhwani, Nitin Ramesh

AU - Tabbarah, Abeer

AU - Hamideh, Dima

AU - Jiang, Liqun

AU - Chen, Liam

AU - Arvanitis, Leonidas D.

AU - Alnajar, Hussein H.

AU - Barber, John R.

AU - Rodríguez-Velasco, Alicia

AU - Orr, Brent

AU - Heaphy, Christopher M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

AB - Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

KW - ATRX

KW - H3-K27M

KW - alternative lengthening of telomeres

KW - glioma

KW - pilocytic astrocytoma

UR - http://www.scopus.com/inward/record.url?scp=85055198744&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055198744&partnerID=8YFLogxK

U2 - 10.1111/bpa.12646

DO - 10.1111/bpa.12646

M3 - Article

VL - 29

SP - 126

EP - 140

JO - Brain Pathology

JF - Brain Pathology

SN - 1015-6305

IS - 1

ER -

Rodriguez FJ, Brosnan-Cashman JA, Allen SJ, Vizcaino MA, Giannini C, Camelo-Piragua S et al. Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia. Brain Pathology. 2019 Jan 1;29(1):126-140. https://doi.org/10.1111/bpa.12646