Somatotroph Tumors and the Epigenetic Status of the <i>GNAS</i> Locus

• Main Authors: Pauline Romanet, 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, Anne Barlier
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: pituitary; <i>GNAS</i>; gsp oncogene; somatotroph; tumorigenesis; epigenetic
• Online Access: https://www.mdpi.com/1422-0067/22/14/7570

Forty percent of somatotroph tumors harbor recurrent activating <i>GNAS</i> mutations, historically called the <i>gsp</i> oncogene. In <i>gsp</i>-negative somatotroph tumors, <i>GNAS</i> expression itself is highly variable; those with <i>GNAS</i> overexpression most resemble phenotypically those carrying the <i>gsp</i> oncogene. <i>GNAS</i> is monoallelically expressed in the normal pituitary due to methylation-based imprinting. We hypothesize that changes in <i>GNAS</i> imprinting of <i>gsp</i>-negative tumors affect <i>GNAS</i> expression levels and tumorigenesis. We characterized the <i>GNAS</i> 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 <i>gsp</i>-negative and <i>gsp</i>-positive tumors in the methylation index at the known differentially methylated region (DMR) of the <i>GNAS</i> A/B transcript promoter, which was confirmed in the larger series of 82 tumors. <i>GNAS</i> allelic expression was analyzed using a polymorphic Fok1 cleavage site in 32 heterozygous <i>gsp</i>-negative tumors. <i>GNAS</i> expression was significantly reduced in the 14 tumors with relaxed <i>GNAS</i> imprinting and biallelic expression, compared to 18 tumors with monoallelic expression. Tumors with relaxed <i>GNAS</i> imprinting showed significantly lower <i>SSTR2</i> and <i>AIP</i> expression levels. Altered A/B DMR methylation was found exclusively in <i>gsp</i>-negative somatotroph tumors. 43% of <i>gsp</i>-negative tumors showed <i>GNAS</i> imprinting relaxation, which correlated with lower <i>GNAS</i>, <i>SSTR2</i> and <i>AIP</i> expression, indicating lower sensitivity to somatostatin analogues and potentially aggressive behavior.