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Article

Somatotroph Tumors and the Epigenetic Status of the GNAS Locus

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Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France
2
Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l’Hypophyse, 94270 Le Kremlin-Bicêtre, Île-de-France, France
3
Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig Maximilian University Munich, 80336 Munich, Germany
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APHM, La Conception Hospital, Laboratory of Molecular Biology, 13385 Marseille, France
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Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Timone Hospital Department of Neurosurgery, 13385 Marseille, France
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Aix Marseille Univ, INSERM, MMG, UMR1251, Marmara Institute, 13385 Marseille, France
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Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014 Paris, France
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Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service d’Anatomie Pathologique et de Neuropathologie, 13385 Marseille, France
9
Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, Department of Endocrinology, Hospital La Conception, 13385 Marseille, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique—Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France
*
Author to whom correspondence should be addressed.
Academic Editors: Camille Tlemsani and Eric Pasmant
Int. J. Mol. Sci. 2021, 22(14), 7570; https://doi.org/10.3390/ijms22147570
Received: 3 June 2021 / Revised: 9 July 2021 / Accepted: 10 July 2021 / Published: 15 July 2021
(This article belongs to the Special Issue Genomics and Epigenetics of Rare Tumors)
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. View Full-Text
Keywords: pituitary; GNAS; gsp oncogene; somatotroph; tumorigenesis; epigenetic; imprinting; relaxation; PitNET pituitary; GNAS; gsp oncogene; somatotroph; tumorigenesis; epigenetic; imprinting; relaxation; PitNET
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MDPI and ACS Style

Romanet, P.; Galluso, J.; Kamenicky, P.; Hage, M.; Theodoropoulou, M.; Roche, C.; Graillon, T.; Etchevers, H.C.; De Murat, D.; Mougel, G.; Figarella-Branger, D.; Dufour, H.; Cuny, T.; Assié, G.; Barlier, A. Somatotroph Tumors and the Epigenetic Status of the GNAS Locus. Int. J. Mol. Sci. 2021, 22, 7570. https://doi.org/10.3390/ijms22147570

AMA Style

Romanet P, Galluso J, Kamenicky P, Hage M, Theodoropoulou M, Roche C, Graillon T, Etchevers HC, De Murat D, Mougel G, Figarella-Branger D, Dufour H, Cuny T, Assié G, Barlier A. Somatotroph Tumors and the Epigenetic Status of the GNAS Locus. International Journal of Molecular Sciences. 2021; 22(14):7570. https://doi.org/10.3390/ijms22147570

Chicago/Turabian Style

Romanet, Pauline, Justine Galluso, Peter Kamenicky, Mirella Hage, Marily Theodoropoulou, Catherine Roche, Thomas Graillon, Heather C. Etchevers, Daniel De Murat, Grégory Mougel, Dominique Figarella-Branger, Henry Dufour, Thomas Cuny, Guillaume Assié, and Anne Barlier. 2021. "Somatotroph Tumors and the Epigenetic Status of the GNAS Locus" International Journal of Molecular Sciences 22, no. 14: 7570. https://doi.org/10.3390/ijms22147570

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