Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

Olivera Casar-Borota; Henning Bünsow Boldt; Britt Edén Engström; Marianne Skovsager Andersen; Bertrand Baussart; Daniel Bengtsson; Katarina Berinder; Bertil Ekman; Ulla Feldt-Rasmussen; Charlotte Höybye; Jens Otto L Jørgensen; Anders Jensen Kolnes; Márta Korbonits; Åse Krogh Rasmussen; John R Lindsay; Paul Benjamin Loughrey; Dominique Maiter; Emilija Manojlovic-Gacic; Jens Pahnke; Pietro Luigi Poliani; Vera Popovic; Oskar Ragnarsson; Camilla Schalin-Jäntti; David Scheie; Miklós Tóth; Chiara Villa; Martin Wirenfeldt; Jacek Kunicki; Pia Burman

doi:10.1210/clinem/dgaa749

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

Olivera Casar-Borota, Henning Bünsow Boldt, Britt Edén Engström, Marianne Skovsager Andersen, Bertrand Baussart, Daniel Bengtsson, Katarina Berinder, Bertil Ekman, Ulla Feldt-Rasmussen, Charlotte Höybye, Jens Otto L Jørgensen, Anders Jensen Kolnes, Márta Korbonits, Åse Krogh Rasmussen, John R Lindsay, Paul Benjamin Loughrey, Dominique Maiter, Emilija Manojlovic-Gacic, Jens Pahnke, Pietro Luigi PolianiVera Popovic, Oskar Ragnarsson, Camilla Schalin-Jäntti, David Scheie, Miklós Tóth, Chiara Villa, Martin Wirenfeldt, Jacek Kunicki, Pia Burman

Patrick G Johnston Centre for Cancer Research

Research output: Contribution to journal › Article › peer-review

54 Citations (Scopus)

107 Downloads (Pure)

Abstract

CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.

OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.

DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.

RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.

CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Original language	English
Pages (from-to)	1183-1194
Number of pages	12
Journal	The Journal of clinical endocrinology and metabolism
Volume	106
Issue number	4
Early online date	27 Oct 2020
DOIs	https://doi.org/10.1210/clinem/dgaa749
Publication status	Published - Apr 2021

Bibliographical note

Keywords

Pituitary
Neuroendocrinology
Cushing's disease
Hypercortisolaemia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1210/clinem/dgaa749Licence: CC BY

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 20.1 MBLicence: CC BY

Clinical, genetic and molecular correlations in pituitary neuroendocrine tumours
Loughrey, P. B. (Author), James, J. (Supervisor), Craig, S. (Supervisor), Korbonits, M. (Supervisor) & Hunter, S. (Supervisor), Dec 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy

Cite this

Casar-Borota, O., Boldt, H. B., Engström, B. E., Andersen, M. S., Baussart, B., Bengtsson, D., Berinder, K., Ekman, B., Feldt-Rasmussen, U., Höybye, C., Jørgensen, J. O. L., Kolnes, A. J., Korbonits, M., Rasmussen, Å. K., Lindsay, J. R., Loughrey, P. B., Maiter, D., Manojlovic-Gacic, E., Pahnke, J., ... Burman, P. (2021). Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations. The Journal of clinical endocrinology and metabolism, 106(4), 1183-1194. https://doi.org/10.1210/clinem/dgaa749

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title = "Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations",

abstract = "CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.",

keywords = "Pituitary, Neuroendocrinology, Cushing's disease, Hypercortisolaemia",

author = "Olivera Casar-Borota and Boldt, {Henning B{\"u}nsow} and Engstr{\"o}m, {Britt Ed{\'e}n} and Andersen, {Marianne Skovsager} and Bertrand Baussart and Daniel Bengtsson and Katarina Berinder and Bertil Ekman and Ulla Feldt-Rasmussen and Charlotte H{\"o}ybye and J{\o}rgensen, {Jens Otto L} and Kolnes, {Anders Jensen} and M{\'a}rta Korbonits and Rasmussen, {{\AA}se Krogh} and Lindsay, {John R} and Loughrey, {Paul Benjamin} and Dominique Maiter and Emilija Manojlovic-Gacic and Jens Pahnke and Poliani, {Pietro Luigi} and Vera Popovic and Oskar Ragnarsson and Camilla Schalin-J{\"a}ntti and David Scheie and Mikl{\'o}s T{\'o}th and Chiara Villa and Martin Wirenfeldt and Jacek Kunicki and Pia Burman",

note = "{\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.",

year = "2021",

month = apr,

doi = "10.1210/clinem/dgaa749",

language = "English",

volume = "106",

pages = "1183--1194",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "4",

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Casar-Borota, O, Boldt, HB, Engström, BE, Andersen, MS, Baussart, B, Bengtsson, D, Berinder, K, Ekman, B, Feldt-Rasmussen, U, Höybye, C, Jørgensen, JOL, Kolnes, AJ, Korbonits, M, Rasmussen, ÅK, Lindsay, JR, Loughrey, PB, Maiter, D, Manojlovic-Gacic, E, Pahnke, J, Poliani, PL, Popovic, V, Ragnarsson, O, Schalin-Jäntti, C, Scheie, D, Tóth, M, Villa, C, Wirenfeldt, M, Kunicki, J & Burman, P 2021, 'Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations', The Journal of clinical endocrinology and metabolism, vol. 106, no. 4, pp. 1183-1194. https://doi.org/10.1210/clinem/dgaa749

TY - JOUR

T1 - Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

AU - Casar-Borota, Olivera

AU - Boldt, Henning Bünsow

AU - Engström, Britt Edén

AU - Andersen, Marianne Skovsager

AU - Baussart, Bertrand

AU - Bengtsson, Daniel

AU - Berinder, Katarina

AU - Ekman, Bertil

AU - Feldt-Rasmussen, Ulla

AU - Höybye, Charlotte

AU - Jørgensen, Jens Otto L

AU - Kolnes, Anders Jensen

AU - Korbonits, Márta

AU - Rasmussen, Åse Krogh

AU - Lindsay, John R

AU - Loughrey, Paul Benjamin

AU - Maiter, Dominique

AU - Manojlovic-Gacic, Emilija

AU - Pahnke, Jens

AU - Poliani, Pietro Luigi

AU - Popovic, Vera

AU - Ragnarsson, Oskar

AU - Schalin-Jäntti, Camilla

AU - Scheie, David

AU - Tóth, Miklós

AU - Villa, Chiara

AU - Wirenfeldt, Martin

AU - Kunicki, Jacek

AU - Burman, Pia

PY - 2021/4

Y1 - 2021/4

N2 - CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

AB - CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

KW - Pituitary

KW - Neuroendocrinology

KW - Cushing's disease

KW - Hypercortisolaemia

U2 - 10.1210/clinem/dgaa749

DO - 10.1210/clinem/dgaa749

M3 - Article

C2 - 33106857

SN - 0021-972X

VL - 106

SP - 1183

EP - 1194

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 4

ER -

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

Abstract

Bibliographical note

Keywords

UN SDGs

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Student theses

Clinical, genetic and molecular correlations in pituitary neuroendocrine tumours

Cite this