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Somatotroph Tumors and the Epigenetic Status of the GNAS Locus

Forty percent of somatotroph tumors harbor recurrent activating GNAS mutations, historically called the gsp oncogene. In gsp-negative somatotroph tumors, GNAS expression itself is highly variable; those with GNAS overexpression most resemble phenotypically those carrying the gsp oncogene. GNAS is mo...

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Autores principales: Romanet, Pauline, Galluso, Justine, Kamenicky, Peter, Hage, Mirella, Theodoropoulou, Marily, Roche, Catherine, Graillon, Thomas, Etchevers, Heather C., De Murat, Daniel, Mougel, Grégory, Figarella-Branger, Dominique, Dufour, Henry, Cuny, Thomas, Assié, Guillaume, Barlier, Anne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306130/
https://www.ncbi.nlm.nih.gov/pubmed/34299200
http://dx.doi.org/10.3390/ijms22147570
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author Romanet, Pauline
Galluso, Justine
Kamenicky, Peter
Hage, Mirella
Theodoropoulou, Marily
Roche, Catherine
Graillon, Thomas
Etchevers, Heather C.
De Murat, Daniel
Mougel, Grégory
Figarella-Branger, Dominique
Dufour, Henry
Cuny, Thomas
Assié, Guillaume
Barlier, Anne
author_facet Romanet, Pauline
Galluso, Justine
Kamenicky, Peter
Hage, Mirella
Theodoropoulou, Marily
Roche, Catherine
Graillon, Thomas
Etchevers, Heather C.
De Murat, Daniel
Mougel, Grégory
Figarella-Branger, Dominique
Dufour, Henry
Cuny, Thomas
Assié, Guillaume
Barlier, Anne
author_sort Romanet, Pauline
collection PubMed
description Forty percent of somatotroph tumors harbor recurrent activating GNAS mutations, historically called the gsp oncogene. In gsp-negative somatotroph tumors, GNAS expression itself is highly variable; those with GNAS overexpression most resemble phenotypically those carrying the gsp oncogene. GNAS is monoallelically expressed in the normal pituitary due to methylation-based imprinting. We hypothesize that changes in GNAS imprinting of gsp-negative tumors affect GNAS expression levels and tumorigenesis. We characterized the GNAS locus in two independent somatotroph tumor cohorts: one of 23 tumors previously published (PMID: 31883967) and classified by pan-genomic analysis, and a second with 82 tumors. Multi-omics analysis of the first cohort identified a significant difference between gsp-negative and gsp-positive tumors in the methylation index at the known differentially methylated region (DMR) of the GNAS A/B transcript promoter, which was confirmed in the larger series of 82 tumors. GNAS allelic expression was analyzed using a polymorphic Fok1 cleavage site in 32 heterozygous gsp-negative tumors. GNAS expression was significantly reduced in the 14 tumors with relaxed GNAS imprinting and biallelic expression, compared to 18 tumors with monoallelic expression. Tumors with relaxed GNAS imprinting showed significantly lower SSTR2 and AIP expression levels. Altered A/B DMR methylation was found exclusively in gsp-negative somatotroph tumors. 43% of gsp-negative tumors showed GNAS imprinting relaxation, which correlated with lower GNAS, SSTR2 and AIP expression, indicating lower sensitivity to somatostatin analogues and potentially aggressive behavior.
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spelling pubmed-83061302021-07-25 Somatotroph Tumors and the Epigenetic Status of the GNAS Locus Romanet, Pauline Galluso, Justine Kamenicky, Peter Hage, Mirella Theodoropoulou, Marily Roche, Catherine Graillon, Thomas Etchevers, Heather C. De Murat, Daniel Mougel, Grégory Figarella-Branger, Dominique Dufour, Henry Cuny, Thomas Assié, Guillaume Barlier, Anne Int J Mol Sci Article Forty percent of somatotroph tumors harbor recurrent activating GNAS mutations, historically called the gsp oncogene. In gsp-negative somatotroph tumors, GNAS expression itself is highly variable; those with GNAS overexpression most resemble phenotypically those carrying the gsp oncogene. GNAS is monoallelically expressed in the normal pituitary due to methylation-based imprinting. We hypothesize that changes in GNAS imprinting of gsp-negative tumors affect GNAS expression levels and tumorigenesis. We characterized the GNAS locus in two independent somatotroph tumor cohorts: one of 23 tumors previously published (PMID: 31883967) and classified by pan-genomic analysis, and a second with 82 tumors. Multi-omics analysis of the first cohort identified a significant difference between gsp-negative and gsp-positive tumors in the methylation index at the known differentially methylated region (DMR) of the GNAS A/B transcript promoter, which was confirmed in the larger series of 82 tumors. GNAS allelic expression was analyzed using a polymorphic Fok1 cleavage site in 32 heterozygous gsp-negative tumors. GNAS expression was significantly reduced in the 14 tumors with relaxed GNAS imprinting and biallelic expression, compared to 18 tumors with monoallelic expression. Tumors with relaxed GNAS imprinting showed significantly lower SSTR2 and AIP expression levels. Altered A/B DMR methylation was found exclusively in gsp-negative somatotroph tumors. 43% of gsp-negative tumors showed GNAS imprinting relaxation, which correlated with lower GNAS, SSTR2 and AIP expression, indicating lower sensitivity to somatostatin analogues and potentially aggressive behavior. MDPI 2021-07-15 /pmc/articles/PMC8306130/ /pubmed/34299200 http://dx.doi.org/10.3390/ijms22147570 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Romanet, Pauline
Galluso, Justine
Kamenicky, Peter
Hage, Mirella
Theodoropoulou, Marily
Roche, Catherine
Graillon, Thomas
Etchevers, Heather C.
De Murat, Daniel
Mougel, Grégory
Figarella-Branger, Dominique
Dufour, Henry
Cuny, Thomas
Assié, Guillaume
Barlier, Anne
Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
title Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
title_full Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
title_fullStr Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
title_full_unstemmed Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
title_short Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
title_sort somatotroph tumors and the epigenetic status of the gnas locus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306130/
https://www.ncbi.nlm.nih.gov/pubmed/34299200
http://dx.doi.org/10.3390/ijms22147570
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