Hypermethylator Phenotype and Ectopic GIP Receptor in GNAS Mutation-Negative Somatotropinomas

• Published in: The journal of clinical endocrinology and metabolism 2019-05, Vol.104 (5), p.1777-1787
• Main Authors: Hage, Mirella, Chaligné, Ronan, Viengchareun, Say, Villa, Chiara, Salenave, Sylvie, Bouligand, Jérôme, Letouzé, Eric, Tosca, Lucie, Rouquette, Alexandra, Tachdjian, Gérard, Parker, Fabrice, Lombès, Marc, Lacroix, André, Gaillard, Stéphan, Chanson, Philippe, Kamenický, Peter
• Format: Article
• Language: English
• Subjects: Acromegaly; Adenoma - genetics; Adenoma - metabolism; Adolescent; Adult; Aged; Alleles; Chromogranins - genetics; Comparative analysis; Comparative Genomic Hybridization; Cytogenetics; Deoxyribonucleic acid; Dextrose; DNA; DNA Methylation; Ectopic expression; Endocrinology and metabolism; Female; Fluorescence in situ hybridization; Gene Expression Regulation, Neoplastic; Gene mutations; Genes; Genetic aspects; Genetic transcription; Gigantism; GIP protein; Glucose; Glucose - metabolism; GNAS protein; Growth Hormone - metabolism; Growth Hormone-Secreting Pituitary Adenoma - genetics; Growth Hormone-Secreting Pituitary Adenoma - metabolism; Growth hormones; GTP-Binding Protein alpha Subunits, Gs - genetics; Human health and pathology; Humans; Insulin-Like Growth Factor I - metabolism; Life Sciences; Male; Methylation; Middle Aged; Mutation; Nuclei; Phenotype; Phenotypes; Pituitary; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; Ribonucleic acid; RNA; Somatotropin; Transcription activation; Tumorigenesis; Tumors; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2018-01504

Abstract Context Besides GNAS gene mutations, the molecular pathogenesis of somatotroph adenomas responsible for gigantism and acromegaly remains elusive. Objective To investigate alternative driver events in somatotroph tumorigenesis, focusing on a subgroup of acromegalic patients with a paradoxical increase in growth hormone (GH) secretion after oral glucose, resulting from ectopic glucose-dependent insulinotropic polypeptide receptor (GIPR) expression in their somatotropinomas. Design, Setting, and Patients We performed combined molecular analyses, including array-comparative genomic hybridization, RNA/DNA fluorescence in situ hybridization, and RRBS DNA methylation analysis on 41 somatotropinoma samples from 38 patients with acromegaly and three sporadic giants. Ten patients displayed paradoxical GH responses to oral glucose. Results GIPR expression was detected in 13 samples (32%), including all 10 samples from patients with paradoxical GH responses. All GIPR-expressing somatotropinomas were negative for GNAS mutations. GIPR expression occurred through transcriptional activation of a single allele of the GIPR gene in all GIPR-expressing samples, except in two tetraploid samples, where expression occurred from two alleles per nucleus. In addition to extensive 19q duplications, we detected in four samples GIPR locus microamplifications in a certain proportion of nuclei. We identified an overall hypermethylator phenotype in GIPR-expressing samples compared with GNAS-mutated adenomas. In particular, we observed hypermethylation in the GIPR gene body, likely driving its ectopic expression. Conclusions We describe a distinct molecular subclass of somatotropinomas, clinically revealed by a paradoxical increase of GH to oral glucose related to pituitary GIPR expression. This ectopic GIPR expression occurred through hypomorphic transcriptional activation and is likely driven by GIPR gene microamplifications and DNA methylation abnormalities. Ectopic GIPR expression in a subset of somatotropinomas occurs through hypomorphic transcriptional activation, likely driven by GIPR gene microamplifications and DNA hypermethylation changes.