{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:58:42Z","timestamp":1771919922310,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T00:00:00Z","timestamp":1626307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Groupement de Recherche CREST-NET","award":["GDR2031"],"award-info":[{"award-number":["GDR2031"]}]},{"name":"Excellence Initiative of Aix Marseille University -A*Midex- a French &quot;Investissement d'Avenir&quot;","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Institut National de lutte contre le Cancer (INCa)","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"MarMaRa Institute","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"French Ministry of Health","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22147570","type":"journal-article","created":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T09:32:07Z","timestamp":1626341527000},"page":"7570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Somatotroph Tumors and the Epigenetic Status of the GNAS Locus"],"prefix":"10.3390","volume":"22","author":[{"given":"Pauline","family":"Romanet","sequence":"first","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justine","family":"Galluso","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kamenicky","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Bic\u00eatre, Service d\u2019Endocrinologie et des Maladies de la Reproduction, Centre de R\u00e9f\u00e9rence des Maladies Rares de l\u2019Hypophyse, 94270 Le Kremlin-Bic\u00eatre, \u00cele-de-France, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirella","family":"Hage","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Bic\u00eatre, Service d\u2019Endocrinologie et des Maladies de la Reproduction, Centre de R\u00e9f\u00e9rence des Maladies Rares de l\u2019Hypophyse, 94270 Le Kremlin-Bic\u00eatre, \u00cele-de-France, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marily","family":"Theodoropoulou","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig Maximilian University Munich, 80336 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Roche","sequence":"additional","affiliation":[{"name":"APHM, La Conception Hospital, Laboratory of Molecular Biology, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Graillon","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Timone Hospital Department of Neurosurgery, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0201-3799","authenticated-orcid":false,"given":"Heather C.","family":"Etchevers","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, MMG, UMR1251, Marmara Institute, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"De Murat","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gr\u00e9gory","family":"Mougel","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Figarella-Branger","sequence":"additional","affiliation":[{"name":"Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service d\u2019Anatomie Pathologique et de Neuropathologie, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Dufour","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Timone Hospital Department of Neurosurgery, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8440-0030","authenticated-orcid":false,"given":"Thomas","family":"Cuny","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, Department of Endocrinology, Hospital La Conception, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillaume","family":"Assi\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014 Paris, France"},{"name":"Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique\u2014H\u00f4pitaux de Paris, H\u00f4pital Cochin, 75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3740-6173","authenticated-orcid":false,"given":"Anne","family":"Barlier","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1159\/000095533","article-title":"Transsphenoidal microsurgery for newly diagnosed acromegaly: A personal view after more than 1,000 operations","volume":"83","author":"Ludecke","year":"2006","journal-title":"Neuroendocrinology"},{"key":"ref_2","first-page":"1174","article-title":"A Comparative Update on the Neuroendocrine Regulation of Growth Hormone in Vertebrates","volume":"11","author":"Unniappan","year":"2021","journal-title":"Front. Endocrinol. Lausanne"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1210\/jc.2007-1986","article-title":"Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas","volume":"93","author":"Albrecht","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/340692a0","article-title":"GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours","volume":"340","author":"Landis","year":"1989","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1126\/science.2116665","article-title":"Two G protein oncogenes in human endocrine tumors","volume":"249","author":"Lyons","year":"1990","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1210\/en.2006-1273","article-title":"Conditional Overexpression of the Wild-Type Gs \u03b1 as the gsp Oncogene Initiates Chronic Extracellularly Regulated Kinase 1\/2 Activation and Hormone Hypersecretion in Pituitary Cell Lines","volume":"148","author":"Romano","year":"2007","journal-title":"Endocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1111\/j.1365-2826.2009.01910.x","article-title":"Signalling pathway alterations in pituitary adenomas: Involvement of Gsalpha, cAMP and mitogen-activated protein kinases","volume":"21","author":"Pertuit","year":"2009","journal-title":"J. Neuroendocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1172\/JCI11887","article-title":"Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly","volume":"107","author":"Hayward","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_9","first-page":"2759","article-title":"Impact of gsp oncogene on the expression of genes coding for G(s)\u03b1, Pit-1, G(i)2\u03b1, and somatostatin receptor 2 in human somatotroph adenomas: Involvement in octreotide sensitivity","volume":"84","author":"Barlier","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1210\/en.2010-1077","article-title":"The gsp oncogene disrupts Ras\/ERK-dependent prolactin gene regulation in gsp inducible somatotroph cell line","volume":"152","author":"Pertuit","year":"2011","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10038","DOI":"10.1073\/pnas.95.17.10038","article-title":"The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins","volume":"95","author":"Hayward","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1093\/hmg\/ddg130","article-title":"Functional polymorphisms in the paternally expressed XL\u03b1s and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation","volume":"12","author":"Freson","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4336","DOI":"10.1210\/jc.2003-030393","article-title":"The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands: Implications for thyroid function in pseudohypoparathyroidism types 1A and 1B","volume":"88","author":"Liu","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1210\/jc.2002-020183","article-title":"The gsalpha gene: Predominant maternal origin of transcription in human thyroid gland and gonads","volume":"87","author":"Mantovani","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5808","DOI":"10.1128\/MCB.20.16.5808-5817.2000","article-title":"Identification of a methylation imprint mark within the mouse Gnas locus","volume":"20","author":"Liu","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI10431","article-title":"A GNAS1 imprinting defect in pseudohypoparathyroidism type IB","volume":"106","author":"Liu","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_17","first-page":"4386","article-title":"Activating mutations of the G(s)\u03b1 gene are associated with low levels of Gs\u03b1 protein in growth hormone-secreting tumors","volume":"83","author":"Mantovani","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1177\/153537020322800904","article-title":"Genetics of pituitary tumors: Focus on G-protein mutations","volume":"228","author":"Lania","year":"2003","journal-title":"Exp. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/ijc.22816","article-title":"Gs alpha overexpression and loss of Gs alpha imprinting in human somatotroph adenomas: Association with tumor size and response to pharmacologic treatment","volume":"121","author":"Picard","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ccell.2019.11.002","article-title":"Pangenomic Classification of Pituitary Neuroendocrine Tumors","volume":"37","author":"Neou","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1079","DOI":"10.1542\/peds.2014-2806","article-title":"Case report of GNAS epigenetic defect revealed by a congenital hypothyroidism","volume":"135","author":"Romanet","year":"2015","journal-title":"Pediatrics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1007\/s12022-016-9460-5","article-title":"Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation","volume":"28","author":"Romanet","year":"2017","journal-title":"Endocr. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1530\/EJE-15-1064","article-title":"Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas","volume":"174","author":"Ronchi","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1677\/ERC-09-0094","article-title":"Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: Pathological and clinical implications","volume":"16","author":"Angelini","year":"2009","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1530\/ERC-13-0043","article-title":"Aip regulates cAMP signalling and GH secretion in GH3 cells","volume":"20","author":"Formosa","year":"2013","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/onc.2014.50","article-title":"AIP inactivation leads to pituitary tumorigenesis through defective G\u03b1i-cAMP signaling","volume":"34","author":"Tuominen","year":"2014","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1530\/ERC-12-0322","article-title":"Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations","volume":"20","author":"Rotondi","year":"2013","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/ng1398","article-title":"A cis -acting control region is required exclusively for the tissue-specific imprinting of Gnas","volume":"36","author":"Williamson","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5513","DOI":"10.1073\/pnas.0408262102","article-title":"From the Cover: Identification of the control region for tissue-specific imprinting of the stimulatory G protein \u03b1-subunit","volume":"102","author":"Liu","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:31:01Z","timestamp":1760164261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,15]]},"references-count":29,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147570"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147570","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,15]]}}}