Genetics of Pituitary Adenoma


Genetic changes of pituitary have been investigated during several decades and have been identified as germ line mutations, including MEN1, PRKAR1A, AIP, CDKN1B and SDHx genes, and somatic mutations including GNAS and PIK3CA genes. In addition to these genetic changes, further novel genes were recently identified related to childhood pituitary tumours including DICER1 and GPR101. And somatic USP8 gene mutations were found in 35–62% of Cushing disease by next‐generation sequencing technique. Furthermore, Genome‐wide association study of pituitary adenomas and whole‐genome sequencing of GH‐secreting adenomas were reported. From the studies of genetically engineered animals which develop pituitary adenomas, predominant genes related to cell cycle (Rb, p27, p18, PTTG1, HMGAs, MEN1 and Cdk4) and cAMP signalling (Prkar1a, D2r, Ghrhr and Aip) have been identified.

Key Concepts

  • Genetic changes in human pituitary adenomas are identified predominantly from germ line mutations of hereditary syndromes.
  • Some genes related to germ line mutations were also identified in somatic mutations.
  • Recent developments of somatic mutations using next‐generation sequencing are updated.
  • Genetically engineered animal models of pituitary adenomas are summarised.
  • Further epigenetic and proteomic analyses are important in pituitary adenomas.

Keywords: pituitary adenomas; genetics; tumourigenesis; cell cycle; cAMP; germ line mutation; somatic mutation

Figure 1. Schema of pituitary adenoma pathogenesis.


Balogh K, Racz K, Patocs A, et al. (2006) Menin and its interacting proteins: elucidation of menin function. Trends in Endocrinology and Metabolism 17: 357–364.

Beckers A, Aaltonen LA, Daly AF, et al. (2013) Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrine Reviews 34: 239–277.

Beckers A, Lodish MB, Trivellin G, et al. (2015) X‐linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocrine‐Related Cancer 22: 353–367.

Bertolino P, Tong WM, Galendo D, et al. (2003) Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Molecular Endocrinology 17: 1880–1892.

Bossis I and Stratakis CA (2004) Minireview: PRKAR1A: normal and abnormal functions. Endocrinology 145: 5452–5458.

Cano DA, Soto‐Moreno A and Leal‐Cerro A (2014) Genetically engineered mouse models of pituitary tumors. Frontiers in Oncology 4: 203.

Chien WM, Rabin S, Macias E, et al. (2006) Genetic mosaics reveal both cell‐autonomous and cell‐nonautonomous function of murine p27Kip1. Proceedings of the National Academy of Sciences of the United States of America 103: 4122–4127.

Correa R, Salpea P and Stratakis CA (2015) Carney complex: an update. European Journal of Endocrinology 173: M85–M97.

Crabtree JS, Scacheri PC, Ward JM, et al. (2001) A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proceedings of the National Academy of Sciences of the United States of America 98: 1118–1123.

de Kock L, Sabbaghian N, Plourde F, et al. (2014) Pituitary blastoma: a pathognomonic feature of germ‐line DICER1 mutations. Acta Neuropathologica 128: 111–122.

Fedele M, Visone R, De Martino I, et al. (2006) HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell 9: 459–471.

Foulkes WD, Priest JR and Duchaine TF (2014) DICER1: mutations, microRNAs and mechanisms. Nature Reviews Cancer 14: 662–672.

Fukuoka H, Cooper O, Ben‐Shlomo A, et al. (2011) EGFR as a therapeutic target for human, canine, and mouse ACTH‐secreting pituitary adenomas. Journal of Clinical Investigation 121: 4712–4721.

Igreja S, Chahal HS, King P, et al. (2010) Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Human Mutation 31: 950–960.

Jacks T, Fazeli A, Schmitt EM, et al. (1992) Effects of an Rb mutation in the mouse. Nature 359: 295–300.

Kiyokawa H, Kineman RD, Manova‐Todorova KO, et al. (1996) Enhanced growth of mice lacking the cyclin‐dependent kinase inhibitor function of p27(Kip1). Cell 85: 721–732.

Lecoq AL, Kamenicky P, Guiochon‐Mantel A, et al. (2015) Genetic mutations in sporadic pituitary adenomas—what to screen for? Nature Reviews Endocrinology 11: 43–54.

Lin Y, Jiang X, Shen Y, et al. (2009) Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocrine‐Related Cancer 16: 301–310.

Liu X, Kano M, Araki T, et al. (2015) ErbB receptor‐driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology 156: 71–79.

Mantovani G, Lania AG and Spada A (2010) GNAS imprinting and pituitary tumors. Molecular and Cellular Endocrinology 326: 15–18.

Melmed S (2011) Pathogenesis of pituitary tumors. Nature Reviews Endocrinology 7: 257–266.

Nakayama K, Ishida N, Shirane M, et al. (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85: 707–720.

Perez‐Rivas LG, Theodoropoulou M, Ferrau F, et al. (2015) The gene of the ubiquitin‐specific protease 8 is frequently mutated in adenomas causing Cushing's disease. Journal of Clinical Endocrinology and Metabolism 100: E997–E1004.

Peverelli E, Mantovani G, Lania AG, et al. (2014) cAMP in the pituitary: an old messenger for multiple signals. Journal of Molecular Endocrinology 52: R67–R77.

Raitila A, Lehtonen HJ, Arola J, et al. (2010) Mice with inactivation of aryl hydrocarbon receptor‐interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. American Journal of Pathology 177: 1969–1976.

Reincke M, Sbiera S, Hayakawa A, et al. (2015) Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature Genetics 47: 31–38.

Sahakitrungruang T, Srichomthong C, Pornkunwilai S, et al. (2014) Germline and somatic DICER1 mutations in a pituitary blastoma causing infantile‐onset Cushing's disease. Journal of Clinical Endocrinology and Metabolism 99: E1487–E1492.

Schernthaner‐Reiter MH, Trivellin G and Stratakis CA (2016) MEN1, MEN4, and Carney complex: pathology and molecular genetics. Neuroendocrinology 103: 18–31.

Thakker RV, Newey PJ, Walls GV, et al. (2012) Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Journal of Clinical Endocrinology and Metabolism 97: 2990–3011.

Thakker RV (2014) Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology 386: 2–15.

Trivellin G, Daly AF, Faucz FR, et al. (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New England Journal of Medicine 371: 2363–2374.

Valimaki N, Demir H, Pitkanen E, et al. (2015) Whole‐genome sequencing of growth hormone (GH)‐secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 100: 3918–3927.

Vierimaa O, Georgitsi M, Lehtonen R, et al. (2006) Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312: 1228–1230.

Vlotides G, Eigler T and Melmed S (2007) Pituitary tumor‐transforming gene: physiology and implications for tumorigenesis. Endocrine Reviews 28: 165–186.

Wang H, Bauzon F, Ji P, et al. (2010) Skp2 is required for survival of aberrantly proliferating Rb1‐deficient cells and for tumorigenesis in Rb1+/− mice. Nature Genetics 42: 83–88.

Weinstein LS, Liu J, Sakamoto A, et al. (2004) Minireview: GNAS: normal and abnormal functions. Endocrinology 145: 5459–5464.

Xekouki P, Szarek E, Bullova P, et al. (2015) Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. Journal of Clinical Endocrinology and Metabolism 100: E710–E719.

Ye Z, Li Z, Wang Y, et al. (2015) Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma. Nature Genetics 47: 793–797.

Yin Z, Williams‐Simons L, Parlow AF, et al. (2008) Pituitary‐specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Molecular Endocrinology 22: 380–387.

Yu S, Asa SL, Weigel RJ, et al. (2003) Pituitary tumor AP‐2alpha recognizes a cryptic promoter in intron 4 of fibroblast growth factor receptor 4. Journal of Biological Chemistry 278: 19597–19602.

Zhao H, Bauzon F, Fu H, et al. (2013) Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer Cell 24: 645–659.

Zhou Y, Zhang X and Klibanski A (2014) Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma. Molecular and Cellular Endocrinology 386: 16–33.

Further Reading

D'Angelo D, Esposito F and Fusco A (2015) Epigenetic mechanisms leading to overexpression of HMGA protein in human pituitary adenomas. Frontiers in Medicine (Lausanne) 2: 39.

Dworakowska, D., and Grossman, AB (2014) The Molecular Genetics of Corticotroph Tumours. In: eLS. John Wiley & Sons Ltd, Chichester, UK. 10.1002/9780470015902.a0024906

Fukuoka H and Takahashi Y (2014) The role of genetic and epigenetic changes in pituitary tumorigenesis. Neurologia Medico‐Chirurfica (Tokyo) 54: 943–957.

Lines KE, Stevenson M and Thakker RV (2016) Animal models of pituitary neoplasia. Molecular and Cellular Endocrinology 5: 68–81.

Murray, RD, and Melmed, S(2006) The Pituitary. In: eLS. John Wiley & Sons Ltd, Chichester, UK. 10.1038/npg.els.0000065

Musat M, Morris DG, Korbonits M, et al. (2010) Cyclins and their related proteins in pituitary tumourigenesis. Molecular and Cellular Endocrinology 326: 25–29.

Newey PJ, Nesbit MA, Thakker RV, et al. (2013) Whole‐exome sequencing studies of nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 98: E796–E800.

Sbiera S, Deutschbein T, Allolio B, et al. (2015) The new molecular landscape of Cushing's disease. Trends in Endocrinology and Metabolism 26: 573–583.

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Fukuoka, Hidenori(Jan 2017) Genetics of Pituitary Adenoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026466]