Telomere alterations in neurofibromatosis type 1-associated solid tumors

Fausto J. Rodriguez; Mindy K. Graham; Jacqueline A. Brosnan-Cashman; John R. Barber; Christine Davis; M. Adelita Vizcaino; Doreen N. Palsgrove; Caterina Giannini; Melike Pekmezci; Sonika Dahiya; Murat Gokden; Michael Noë; Laura D. Wood; Christine A. Pratilas; Carol D. Morris; Allan Belzberg; Jaishri Blakeley; Christopher M. Heaphy

doi:10.1186/s40478-019-0792-5

Telomere alterations in neurofibromatosis type 1-associated solid tumors

Fausto J. Rodriguez, Mindy K. Graham, Jacqueline A. Brosnan-Cashman, John R. Barber, Christine Davis, M. Adelita Vizcaino, Doreen N. Palsgrove, Caterina Giannini, Melike Pekmezci, Sonika Dahiya, Murat Gokden, Michael Noë, Laura D. Wood, Christine A. Pratilas, Carol D. Morris, Allan Belzberg, Jaishri Blakeley, Christopher M. Heaphy

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Abstract

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.

Original language	English
Pages (from-to)	139
Number of pages	1
Journal	Acta Neuropathologica Communications
Volume	7
Issue number	1
DOIs	https://doi.org/10.1186/s40478-019-0792-5
State	Published - Aug 28 2019

Keywords

ATRX
Alternative lengthening of telomeres
Glioma
MPNST
NF1

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10.1186/s40478-019-0792-5

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Rodriguez, F. J., Graham, M. K., Brosnan-Cashman, J. A., Barber, J. R., Davis, C., Vizcaino, M. A., Palsgrove, D. N., Giannini, C., Pekmezci, M., Dahiya, S., Gokden, M., Noë, M., Wood, L. D., Pratilas, C. A., Morris, C. D., Belzberg, A., Blakeley, J., & Heaphy, C. M. (2019). Telomere alterations in neurofibromatosis type 1-associated solid tumors. Acta Neuropathologica Communications, 7(1), 139. https://doi.org/10.1186/s40478-019-0792-5

@article{0861debea90243fa929f5a318562c53c,

title = "Telomere alterations in neurofibromatosis type 1-associated solid tumors",

abstract = "The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.",

keywords = "ATRX, Alternative lengthening of telomeres, Glioma, MPNST, NF1",

author = "Rodriguez, {Fausto J.} and Graham, {Mindy K.} and Brosnan-Cashman, {Jacqueline A.} and Barber, {John R.} and Christine Davis and Vizcaino, {M. Adelita} and Palsgrove, {Doreen N.} and Caterina Giannini and Melike Pekmezci and Sonika Dahiya and Murat Gokden and Michael No{\"e} and Wood, {Laura D.} and Pratilas, {Christine A.} and Morris, {Carol D.} and Allan Belzberg and Jaishri Blakeley and Heaphy, {Christopher M.}",

note = "Funding Information: This work was supported in part by Pilocytic/Pilomyxoid Fund, including Lauren{\textquoteright}s First and Goal, and the Stick it to Brain Tumors Annual Women{\textquoteright}s Ice Hockey Tournament (FJR), the Basic/Translational Science Investigator Award from the North American Neuroendocrine Tumor Society supported by the Neuroendocrine Tumor Research Foundation (CMH), a collaborative grant between the Wilmer Eye Institute (Baltimore, MD) and the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia (to FJR), Department of Defense grant W81XWH-18-1-0496 (FJR), NIH grant 2T32CA009110-39A1 (JAB), and NIH grant P30 CA006973 to the Sidney Kimmel Comprehensive Cancer Center (PI: W. Nelson).",

year = "2019",

month = aug,

day = "28",

doi = "10.1186/s40478-019-0792-5",

language = "English",

volume = "7",

pages = "139",

journal = "Acta Neuropathologica Communications",

issn = "2051-5960",

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Rodriguez, FJ, Graham, MK, Brosnan-Cashman, JA, Barber, JR, Davis, C, Vizcaino, MA, Palsgrove, DN, Giannini, C, Pekmezci, M, Dahiya, S, Gokden, M, Noë, M, Wood, LD, Pratilas, CA, Morris, CD, Belzberg, A, Blakeley, J & Heaphy, CM 2019, 'Telomere alterations in neurofibromatosis type 1-associated solid tumors', Acta Neuropathologica Communications, vol. 7, no. 1, pp. 139. https://doi.org/10.1186/s40478-019-0792-5

TY - JOUR

T1 - Telomere alterations in neurofibromatosis type 1-associated solid tumors

AU - Rodriguez, Fausto J.

AU - Graham, Mindy K.

AU - Brosnan-Cashman, Jacqueline A.

AU - Barber, John R.

AU - Davis, Christine

AU - Vizcaino, M. Adelita

AU - Palsgrove, Doreen N.

AU - Giannini, Caterina

AU - Pekmezci, Melike

AU - Dahiya, Sonika

AU - Gokden, Murat

AU - Noë, Michael

AU - Wood, Laura D.

AU - Pratilas, Christine A.

AU - Morris, Carol D.

AU - Belzberg, Allan

AU - Blakeley, Jaishri

AU - Heaphy, Christopher M.

N1 - Funding Information: This work was supported in part by Pilocytic/Pilomyxoid Fund, including Lauren’s First and Goal, and the Stick it to Brain Tumors Annual Women’s Ice Hockey Tournament (FJR), the Basic/Translational Science Investigator Award from the North American Neuroendocrine Tumor Society supported by the Neuroendocrine Tumor Research Foundation (CMH), a collaborative grant between the Wilmer Eye Institute (Baltimore, MD) and the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia (to FJR), Department of Defense grant W81XWH-18-1-0496 (FJR), NIH grant 2T32CA009110-39A1 (JAB), and NIH grant P30 CA006973 to the Sidney Kimmel Comprehensive Cancer Center (PI: W. Nelson).

PY - 2019/8/28

Y1 - 2019/8/28

N2 - The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.

AB - The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.

KW - ATRX

KW - Alternative lengthening of telomeres

KW - Glioma

KW - MPNST

KW - NF1

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U2 - 10.1186/s40478-019-0792-5

DO - 10.1186/s40478-019-0792-5

M3 - Article

C2 - 31462295

AN - SCOPUS:85071630752

SN - 2051-5960

VL - 7

SP - 139

JO - Acta Neuropathologica Communications

JF - Acta Neuropathologica Communications

IS - 1

ER -

Telomere alterations in neurofibromatosis type 1-associated solid tumors

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Keywords

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