title: Novel Genetic Causes of Pituitary Adenomas.
abstract: Recently, a number of novel genetic alterations have been identified that predispose individuals to pituitary adenomas. Clinically relevant pituitary adenomas are relatively common, present in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior lobe of the pituitary gland, and cause disease due to hormonal alterations and local space-occupying effects. The pathomechanism of pituitary adenomas includes alterations in cell-cycle regulation and growth factor signaling, which are mostly due to epigenetic changes; somatic and especially germline mutations occur more rarely. A significant proportion of growth hormone- and adrenocorticotrophin-secreting adenomas have activating somatic mutations in the GNAS and USP8 genes, respectively. Rarely, germline mutations predispose to pituitary tumorigenesis, often in a familial setting. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and McCune-Albright syndrome. Pituitary tumors have also been described in association with neurofibromatosis type 1, DICER1 syndrome, and SDHx mutations. Pituitary adenomas with no other associated tumors have been described as familial isolated pituitary adenomas. Patients with AIP or GPR101 mutations often present with pituitary gigantism either in a familial or simplex setting. GNAS and GPR101 mutations that arise in early embryonic age can lead to somatic mosaicism involving the pituitary gland and resulting in growth hormone excess. Senescence has been suggested as the key mechanism protecting pituitary adenomas turning malignant in the overwhelming majority of cases. Here we briefly summarize the genetic background of pituitary adenomas, with an emphasis on the recent developments in this field. Clin Cancer Res; 22(20); 5030-42. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Francisca
authors.initials: F
authors.lastname: Caimari
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. m.korbonits@qmul.ac.uk.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D002864:Chromogranins / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D010903:Pituitary Gland, Anterior / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: D002864:Chromogranins; D056827:Endosomal Sorting Complexes Required for Transport; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs