Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
In: ISSN: 1661-6596, 2021
Online
academicJournal
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International audience ; Background: 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. Methods: 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. Results: 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. Conclusion: 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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Somatotroph Tumors and the Epigenetic Status of the GNAS Locus
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Autor/in / Beteiligte Person: | Romanet, Pauline ; Galluso, Justine ; Kamenicky, Peter ; Hage, Mirella ; Theodoropoulou, Marily ; Roche, Catherine ; Graillon, Thomas ; Etchevers, Heather ; de Murat, Daniel ; Mougel, Grégory ; Figarella-Branger, Dominique ; Dufour, Henry ; Cuny, Thomas ; Assié, Guillaume ; Barlier, Anne, A. ; Marseille medical genetics - Centre de génétique médicale de Marseille (MMG) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Institut Marseille Maladies Rares (MarMaRa) ; Aix Marseille Université (AMU) ; Service d'endocrinologie, diabète, maladies métaboliques Hôpital de la Conception - APHM ; Laboratoire de Biochimie et de Biologie Moléculaire Hôpital de la Conception -, APHM ; Hôpital de la Conception CHU - APHM (LA CONCEPTION) ; Paris-Saclay, Université ; Physiologie et physiopathologie endocriniennes (PHYSENDO) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay ; AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre) ; Ludwig Maximilian University Munich = Ludwig Maximilians Universität München (LMU) ; Neurologie, maladies neuro-musculaires Hôpital de la Timone - APHM ; Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone CHU - APHM (TIMONE) ; Institut Cochin (IC UM3 (UMR 8104 / U1016)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) ; Institut de neurophysiopathologie (INP) ; Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS) ; Hôpital de la Timone CHU - APHM (TIMONE) ; All phases of this study were supported by grants from the Institut National de lutte contrele Cancer (INCa), and the French Ministry of Health. The project resulting in this publication receivedfunding from the Groupement de Recherche CREST-NET (GDR2031) and Excellence Initiative of AixMarseille University—A*Midex—a French “Investissement d’Avenir”—Institute MarMaRa AMX-19-IET- 007. |
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Zeitschrift: | ISSN: 1661-6596, 2021 |
Veröffentlichung: | HAL CCSD ; MDPI, 2021 |
Medientyp: | academicJournal |
DOI: | 10.3390/ijms22147570 |
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