Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas

Abstract

Pituitary adenomas are benign tumors with variable functional characteristics that can have a significant impact on patients. The majority arise sporadically, but an inherited genetic susceptibility is increasingly being recognized. Recent advances in genetics have widened the scope of our understanding of pituitary tumorigenesis. The clinical and genetic characteristics of pituitary adenomas that develop in the setting of germline-mosaic and somatic GNAS mutations (McCune–Albright syndrome and sporadic acromegaly), germline MEN1 mutations (multiple endocrine neoplasia type 1), and germline PRKAR1A mutations (Carney complex) have been well described. Non-syndromic familial cases of isolated pituitary tumors can occur as familial isolated pituitary adenomas (FIPA); mutations/deletions of the AIP gene have been found in a minority of these. Genetic alterations in GPR101 have been identified recently as causing X-linked acro-gigantism (X-LAG) leading to very early-onset pediatric gigantism. Associations of pituitary adenomas with other tumors have been described in syndromes like multiple endocrine neoplasia type 4, pheochromocytoma-paraganglioma with pituitary adenoma association (3PAs) syndrome and some of their genetic causes have been elucidated. The genetic etiologies of a significant proportions of sporadic corticotropinomas have recently been identified with the discovery of USP8 and USP48 mutations. The elucidation of genetic and molecular pathophysiology in pituitary adenomas is a key factor for better patient management and effective follow-up.

Key words

pituitary adenoma - GNAS - AIP - USP8 - MEN1 - GPR101 - Carney complex - X-LAG - FIPA

Publication History

Received: 14 August 2019

Accepted: 11 March 2020

Article published online:
16 April 2020

• References

• 1 Ostrom QT, Gittleman H, Truitt G. et al. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol 2018; 20: iv1-iv86
• 2 Ezzat S, Asa SL, Couldwell WT. et al. The prevalence of pituitary adenomas: a systematic review. Cancer 2004; 101: 613-619
• 3 Daly AF, Rixhon M, Adam C. et al. High prevalence of pituitary adenomas: A cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 2006; 91: 4769-4775
• 4 Fontana E, Gaillard R. Epidemiology of pituitary adenoma: Results of the first Swiss study. Rev Med Suisse 2009; 5: 2172-2174
• 5 Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: A community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 2010; 72: 377-382
• 6 Gruppetta M, Mercieca C, Vassallo J. Prevalence and incidence of pituitary adenomas: A population based study in Malta. Pituitary 2013; 16: 545-553
• 7 Herman V, Fagin J, Gonsky R. et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990; 71: 1427-1433
• 8 Daly AF, Tichomirowa MA, Beckers A. The epidemiology and genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 2009; 23: 543-554
• 9 Landis CA, Masters SB, Spada A. et al. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989; 340: 692-696
• 10 Xekouki P, Azevedo M, Stratakis CA. Anterior pituitary adenomas: Inherited syndromes, novel genes and molecular pathways. Expert Rev Endocrinol Metab 2010; 5: 697-709
• 11 Taboada GF, Tabet AL, Naves LA. et al. Prevalence of gsp oncogene in somatotropinomas and clinically non-functioning pituitary adenomas: Our experience. Pituitary 2009; 12: 165-169
• 12 Riminucci M, Collins MT, Lala R. et al. An R201H activating mutation of the GNAS1 (Gsalpha) gene in a corticotroph pituitary adenoma. Mol Pathol 2002; 55: 58-60
• 13 Spada A, Arosio M, Bochicchio D. et al. Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 1990; 71: 1421-1426
• 14 Picard C, Silvy M, Gerard C. et al. Gs alpha overexpression and loss of Gs alpha imprinting in human somatotroph adenomas: Association with tumor size and response to pharmacologic treatment. Int J Cancer 2007; 121: 1245-1252
• 15 McCune DJ. Osteita fibrosa cystica : the case of nine-year-old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis. Children 1936; 52: 743-744
• 16 Vasilev V, Daly AF, Thiry A. et al. McCune-Albright syndrome: A detailed pathological and genetic analysis of disease effects in an adult patient. J Clin Endocrinol Metab 2014; 99: E2029-E2038
• 17 Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012 7. (Suppl 1): S4
• 18 Mantovani G, Bondioni S, Lania AG. et al. Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab 2004; 89: 3007-3009
• 19 Ruggieri P, Sim FH, Bond JR. et al. Malignancies in fibrous dysplasia. Cancer 1994; 73: 1411-1424
• 20 Volkl TM, Dorr HG. McCune-Albright syndrome: Clinical picture and natural history in children and adolescents. J Pediatr Endocrinol Metab 2006; 19 (Suppl 2) 551-559
• 21 Akintoye SO, Kelly MH, Brillante B. et al. Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome. J Clin Endocrinol Metab 2006; 91: 2960-2966
• 22 Reincke M, Sbiera S, Hayakawa A. et al. Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nat Genet 2015; 47: 31-38
• 23 Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 2009; 78: 363-397
• 24 Meijer IM, Kerperien J, Sotoca AM. et al. The Usp8 deubiquitination enzyme is post-translationally modified by tyrosine and serine phosphorylation. Cell Signal 2013; 25: 919-930
• 25 Faucz FR, Tirosh A, Tatsi C. et al. Somatic USP8 gene mutations are a common cause of pediatric cushing disease. J Clin Endocrinol Metab 2017; 102: 2836-2843
• 26 Albani A, Theodoropoulou M, Reincke M. Genetics of Cushingʼs disease. Clin Endocrinol (Oxf) 2018; 88: 3-12
• 27 Hayashi K, Inoshita N, Kawaguchi K. et al. The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushingʼs disease. Eur J Endocrinol 2016; 174: 213-226
• 28 Cohen M, Persky R, Stegemann R. et al. Germline USP8 mutation associated with pediatric Cushing disease and other clinical features: A new syndrome. J Clin Endocrinol Metab 2019; 104: 4676-4682
• 29 Hernandez-Ramirez LC, Gam R, Valdes N. et al. Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushingʼs disease. Endocr Relat Cancer 2017; 24: 379-392
• 30 Roussel-Gervais A, Couture C, Langlais D. et al. The Cables1 gene in glucocorticoid regulation of pituitary corticotrope growth and cushing disease. J Clin Endocrinol Metab 2016; 101: 513-522
• 31 Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386: 2-15
• 32 Larsson C, Skogseid B, Oberg K. et al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988; 332: 85-87
• 33 Chandrasekharappa SC, Guru SC, Manickam P. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997; 276: 404-407
• 34 Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): Analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 2008; 29: 22-32
• 35 Falchetti A. Genetics of multiple endocrine neoplasia type 1 syndrome: Whatʼs new and what's old. [version 1; peer review: 3 approved]. F1000 Research 2017, 6 (F1000 Faculty Rev): 73
• 36 Falchetti A, Marini F, Luzi E. et al. Multiple endocrine neoplasms. Best Pract Res Clin Rheumatol 2008; 22: 149-163
• 37 Marini F, Falchetti A, Del Monte F. et al. Multiple endocrine neoplasia type 1. Orphanet J Rare Dis 2006; 1: 38
• 38 Syro LV, Scheithauer BW, Kovacs K. et al. Pituitary tumors in patients with MEN1 syndrome. Clinics (Sao Paulo) 2012; 67 (Suppl. 01) 43-48
• 39 Scheithauer BW, Laws ER, Kovacs K. et al. Pituitary adenomas of the multiple endocrine neoplasia type I syndrome. Semin Diagn Pathol 1987; 4: 205-211
• 40 Verges B, Boureille F, Goudet P. et al. Pituitary disease in MEN type 1 (MEN1): Data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab 2002; 87: 457-465
• 41 Kamilaris CDC, Faucz FR, Voutetakis A. et al. Carney Complex. Exp Clin Endocrinol Diabetes 2019; 127: 156-164
• 42 Kirschner LS, Carney JA, Pack SD. et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26: 89-92
• 43 Robinson-White A, Meoli E, Stergiopoulos S. et al. PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex. J Clin Endocrinol Metab 2006; 91: 2380-2388
• 44 Stratakis CA, Carney JA, Lin JP. et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996; 97: 699-705
• 45 Forlino A, Vetro A, Garavelli L. et al. PRKACB and Carney complex. N Engl J Med 2014; 370: 1065-1067
• 46 Boikos SA, Stratakis CA. Carney complex: The first 20 years. Curr Opin Oncol 2007; 19: 24-29
• 47 Kirschner LS. PRKAR1A and the evolution of pituitary tumors. Mol Cell Endocrinol 2010; 326: 3-7
• 48 Pepe S, Korbonits M, Iacovazzo D. Germline and mosaic mutations causing pituitary tumours: Genetic and molecular aspects. J Endocrinol 2019; 240: R21-R45
• 49 Bertherat J, Horvath A, Groussin L. et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): Phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 2009; 94: 2085-2091
• 50 Pellegata NS, Quintanilla-Martinez L, Siggelkow H. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 2006; 103: 15558-15563
• 51 Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and CDKN1B mutations: The latest of the MEN syndromes. Endocr Relat Cancer 2017; 24: T195-T208
• 52 Frederiksen A, Rossing M, Hermann P. et al. Clinical Features of Multiple Endocrine Neoplasia Type 4 - Novel pathogenic variant and review of published cases. J Clin Endocrinol Metab 2019; 104: 3637-3646
• 53 Lee M, Pellegata NS. Multiple endocrine neoplasia type 4. Front Horm Res 2013; 41: 63-78
• 54 Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 2009; 94: 1826-1834
• 55 Daly AF, Jaffrain-Rea ML, Ciccarelli A. et al. Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab 2006; 91: 3316-3323
• 56 Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 2007; 157: 371-382
• 57 Beckers A, Aaltonen LA, Daly AF. et al. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 2013; 34: 239-277
• 58 Marques NV, Kasuki L, Coelho MC. et al. Frequency of familial pituitary adenoma syndromes among patients with functioning pituitary adenomas in a reference outpatient clinic. J Endocrinol Invest 2017; 40: 1381-1387
• 59 Vierimaa O, Georgitsi M, Lehtonen R. et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006; 312: 1228-1230
• 60 Daly AF, Tichomirowa MA, Petrossians P. et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: An International Collaborative Study. J Clin Endocrinol Metab 2010; 95: E373-E383
• 61 Hernandez-Ramirez LC, Gabrovska P, Denes J. et al. Landscape of familial isolated and young-onset pituitary adenomas: Prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab 2015; 100: E1242-E1254
• 62 Lecoq AL, Kamenicky P, Guiochon-Mantel A. et al. Genetic mutations in sporadic pituitary adenomas–what to screen for?. Nat Rev Endocrinol 2015; 11: 43-54
• 63 Beckers A, Petrossians P, Hanson J, Daly AF. The causes and consequences of pituitary gigantism. Nat Rev Endocrinol 2018; 14: 705-720
• 64 Ozfirat Z, Korbonits M. AIP gene and familial isolated pituitary adenomas. Mol Cell Endocrinol 2010; 326: 71-79
• 65 Formosa R, Borg J, Vassallo J. Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas. Endocr Relat Cancer 2017; 24: 445-457
• 66 Kazlauskas A, Poellinger L, Pongratz I. The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor. J Biol Chem 2000; 275: 41317-41324
• 67 Tuominen I, Heliovaara E, Raitila A. et al. AIP inactivation leads to pituitary tumorigenesis through defective Galphai-cAMP signaling. Oncogene 2015; 34: 1174-1184
• 68 Hernandez-Ramirez LC, Trivellin G, Stratakis CA. Role of Phosphodiesterases on the Function of Aryl Hydrocarbon Receptor-Interacting Protein (AIP) in the Pituitary Gland and on the Evaluation of AIP Gene Variants. Horm Metab Res 2017; 49: 286-295
• 69 Schernthaner-Reiter MH, Trivellin G, Stratakis CA. Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). Hum Mol Genet 2018; 27: 2604-2613
• 70 Hernandez-Ramirez LC, Morgan RML, Barry S. et al. Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland. Oncotarget 2018; 9: 9177-9198
• 71 Rostomyan L, Potorac I, Beckers P. et al. AIP mutations and gigantism. Ann Endocrinol (Paris) 2017; 78: 123-130
• 72 Trivellin G, Daly AF, Faucz FR. et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371: 2363-2374
• 78 Beckers A, Lodish MB, Trivellin G. et al. X-linked acrogigantism syndrome: Clinical profile and therapeutic responses. Endocr Relat Cancer 2015; 22: 353-367
• 73 Iacovazzo D, Caswell R, Bunce B. et al. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun 2016; 4: 56
• 74 Trivellin G, Bjelobaba I, Daly AF. et al. Characterization of GPR101 transcript structure and expression patterns. J Mol Endocrinol 2016; 57: 97-111
• 75 Daly AF, Lysy PA, Desfilles C. et al. GHRH excess and blockade in X-LAG syndrome. Endocr Relat Cancer 2016; 23: 161-170
• 76 Beckers A, Rostomyan L, Potorac I. et al. X-LAG: How did they grow so tall?. Ann Endocrinol (Paris) 2017; 78: 131-136
• 77 Daly AF, Yuan B, Fina F. et al. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocr Relat Cancer 2016; 23: 221-233
• 79 Xekouki P, Pacak K, Almeida M. et al. Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: A new association for SDH?. J Clin Endocrinol Metab 2012; 97: E357-E366
• 80 Xekouki P, Szarek E, Bullova P. et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab 2015; 100: E710-E719
• 81 Hernandez-Ramirez LC, Stratakis CA. Genetics of Cushingʼs Syndrome. Endocrinol Metab Clin North Am 2018; 47: 275-297
• 82 O'Toole SM, Denes J, Robledo M. et al. 15 Years of Paraganglioma: The association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer 2015; 22: T105-T122
• 83 Selak MA, Armour SM, MacKenzie ED. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005; 7: 77-85
• 84 Letouze E, Martinelli C, Loriot C. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 2013; 23: 739-752
• 85 Mannelli M, Canu L, Ercolino T. et al. Diagnosis of Endocrine Disease: SDHx mutations: beyond pheochromocytomas and paragangliomas. Eur J Endocrinol 2018; 178: R11-R17
• 86 Tufton N, Roncaroli F, Hadjidemetriou I. et al. Pituitary carcinoma in a patient with an SDHB mutation. Endocr Pathol 2017; 28: 320-325
• 87 Denes J, Swords F, Rattenberry E. et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: Rresults from a large patient cohort. J Clin Endocrinol Metab 2015; 100: E531-E541
• 88 Daly AF, Castermans E, Oudijk L. et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr Relat Cancer 2018; 25: L37-L42
• 89 Williams VC, Lucas J, Babcock MA. et al. Neurofibromatosis type 1 revisited. Pediatrics 2009; 123: 124-133
• 90 Hannah-Shmouni F, Trivellin G, Stratakis CA. Genetics of gigantism and acromegaly. Growth Horm IGF Res 2016; 30–31: 37-41
• 91 Schultz KAP, Williams GM, Kamihara J. et al. DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res 2018; 24: 2251-2261
• 92 de Kock L, Sabbaghian N, Plourde F. et al. Pituitary blastoma: A pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol 2014; 128: 111-122
• 93 Solarski M, Rotondo F, Foulkes WD. et al. DICER1 gene mutations in endocrine tumors. Endocr Relat Cancer 2018; 25: R197-R208
• 94 Scheithauer BW, Kovacs K, Horvath E. et al. Pituitary blastoma. Acta Neuropathol 2008; 116: 657-666
• 95 Lam HC, Nijmeh J, Henske EP. New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex. J Pathol 2017; 241: 219-225
• 96 Tigas S, Carroll PV, Jones R. et al. Simultaneous Cushingʼs disease and tuberous sclerosis; a potential role for TSC in pituitary ontogeny. Clin Endocrinol (Oxf) 2005; 63: 694-695
• 97 Nandagopal R, Vortmeyer A, Oldfield EH. et al. Cushing's syndrome due to a pituitary corticotropinoma in a child with tuberous sclerosis: An association or a coincidence?. Clin Endocrinol (Oxf) 2007; 67: 639-641