Sporadic multiple endocrine neoplasia type 1 (MEN1) is defined as the occurrence of tumours in two of three main endocrine tissue types: parathyroid, pituitary and pancreaticoduodenal. A prolactinoma variant or Burin variant of MEN1 was found to occur in three large kindreds, with more prolactinomas and fewer gastrinomas than typical MEN1. MEN1 tumours differ from common tumours by showing features from the MEN1 gene (e.g. larger pituitary tumours). They also show various expressions of tumour multiplicity; however, pituitary tumour in MEN1 is usually solitary. Diagnosis in MEN1 carriers during childhood is not directed at cancers but at benign morbid tumours. Morbid prolactinoma occurred at the age of 5 years in one MEN1 individual; hence, this is the earliest age at which to recommend tumour surveillance in carriers. The MEN1 gene shows biallelic inactivation in 30% of some types of common variety endocrine tumours (e.g. parathyroid adenoma, gastrinoma, insulinoma and bronchial carcinoid), but in only 1–5% of common pituitary tumours. Heterozygous knockout of MEN1 in mice provides a robust model of MEN1 and has been found to support further research on anti-angiogenesis therapy for pituitary tumours. The rarity of MEN1 mutations in some MEN1-like states aids the identification of other mutated genes, such as AIP, HRPT2 and p27Kip1. We present recent clinical and basic findings about the MEN1 gene, particularly concerning hereditary vs. common variety pituitary tumours.

Keywords:
Angiogenesis, MEN1, Mouse, p27Kip1, Pituitary tumour, Prolactinoma, Tumour suppressor
1.
Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ: Guidelines for diagnosis and therapy of multiple endocrine neoplasia type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–5671.
2.
Gagel RF, Marx SJ: Multiple endocrine neoplasia; in Kronenberg HM, Melmed S, Polonsky KS, Reed Larsen P (eds): Williams Textbook of Endocrinology, ed 11. Philadelphia, Saunders, 2007, pp 1705–1746.
3.
Vergès B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chambe B, Montvernay C, Calender A: Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab 2002;87:457–465.
4.
Farid NR, Buehler A, Russell NA, Maroun FB, Allerdice P, Smyth HS: Prolactinomas in familial multiple endocrine neoplasia syndrome type 1. Am J Med 1980;69:874–880.
5.
Petty EM, Green JS, Marx SJ, Taggart RT, Farid N, Bale AE: Mapping the gene for hereditary hyperparathyroidism and prolactinoma (MEN1-Burin) to chromosome 11q: evidence for a founder effect in patients from Newfoundland. Am J Hum Genet 1994;54:1060–1066.
6.
Olufemi SE, Green JS, Manickam P, Guru SC, Agarwal SK, Kester MB, Dong Q, Burns AL, Spiegel AM, Marx SJ, Collins FS, Chandrasekharappa SC: Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland. Hum Mutat 1998;11:264–269.
7.
Hao W, Skarulis MC, Simonds WF, Weinstein LS, Agarwal SK, Mateo C, James-Newton L, Hobbs GR, Gibril F, Jensen RT, Marx SJ: MEN1 variant with frequent prolactinoma and rare gastrinoma. J Clin Endocrinol Metab 2004;89:3776–3784.
8.
Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M: Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988;332:85–87.
9.
Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gündogdu S, De Menis E, Mäkinen MJ, Launonen V, Karhu A, Aaltonen LA: Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006;312:1228–1230.
10.
Beckers A, Daly AF: The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 2007;157:371–382.
11.
Daly AF, Tichomirowa MA, Beckers A: Genetic, molecular and clinical features of familial isolated pituitary adenomas. Horm Res 2009;71(suppl 2):116–122.
12.
Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, Marx SJ: Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002;81: 1–26.
13.
Warner J, Epstein M, Sweet A, Singh D, Burgess J, Stranks S, Hill P, Perry-Keene D, Learoyd D, Robinson B, Birdsey P, Mackenzie E, Teh BT, Prins JB, Cardinal J: Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 2004;41:155–160.
14.
Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ: Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 2004;89:96–102.
15.
Warner J, Nyholt DR, Busfield F, Epstein M, Burgess J, Stranks S, Hill P, Perry-Keene D, Learoyd D, Robinson B, Teh BT, Prins JB, Cardinal JW: Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3-14. J Med Genet 2006;43:e12.
16.
Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamburrano G, Avenia N, Daddi G, Puma F, Ribacchi R, Santeusanio F, Angeletti G, Brandi ML: Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab 2005;90:2603–2609.
17.
Yeatman TJ, Sharp JV, Kimura AK: Can susceptibility to carcinoid tumors be inherited? Cancer 1989;3:390–393.
18.
Babovic-Vuksanovic D, Constantinou CL, Rubin J, Rowland CM, Schaid DJ, Karnes PS: Familial occurrence of carcinoid tumors and association with other malignant neoplasms. Cancer Epidemiol Biomarkers Prev 1999;8:715–719.
19.
Oliveira AM, Tazelaar HD, Wentzlaff KA, Kosugi NS, Hai N, Benson A, Miller DL, Yang P: Familial pulmonary carcinoid tumors. Cancer 2001;91:2104–2109.
20.
Hemminki K, Li X: Familial carcinoid tumors and subsequent cancers: a nation-wide epidemiologic study from Sweden. Int J Cancer 2001;94:444–448.
21.
Franklin DS, Godfrey VL, O’Brien DA, Deng C, Xiong Y: Functional collaboration between different cyclin-dependent kinase inhibitors suppress tumor growth with distinct tissue specificity. Mol Cell Biol 2000;20:6147–6158.
22.
Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Höfler H, Fend F, Graw J, Atkinson MJ: Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 2006;103:15558–15563 [erratum in Proc Natl Acad Sci USA 2006;103:19213].
23.
Georgitsi M, Raitila A, Karhu A, van der Luijt RB, Aalfs CM, Sane T, Vierimaa O, Mäkinen MJ, Tuppurainen K, Paschke R, Gimm O, Koch CA, Gündogdu S, Lucassen A, Tischkowitz M, Izatt L, Aylwin S, Bano G, Hodgson S, De Menis E, Launonen V, Vahteristo P, Aaltonen LA: Germline CDKN1B/p27KIP1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 2007;92:3321–3325.
24.
Ozawa A, Agarwal SK, Mateo CM, Burns AL, Rice TS, Kennedy PA, Quigley CM, Simonds WF, Weinstein LS, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ: The parathyroid/pituitary variant of MEN1 usually has causes other than p27 Kip1 mutations. J Clin Endocrinol Metab 2007;92:1948–1951.
25.
Online Mendelian Inheritance of Man (OMIM): Multiple Endocrine Neoplasia, Type IV; MEN4; #610755. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610755. Creation date 2/12/2007, updated 5/3/2007. Last accessed 27 November 2008.
26.
Agarwal SK, Mateo C, Marx SJ: Rare germline mutations in cyclin-dependent kinase inhibitor genes in MEN1 and related states. J Clin Endocrinol Metab DOI 10.1210/jc.2008-2083.
27.
Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE: The consensus coding sequences of human breast and colorectal cancers. Science 2006;314:268–274.
28.
Arnold A, Marx SJ: Familial hyperparathyroidism; in Rosen C (ed): Primer on the Metabolic Bone Diseases and Mineral Metabolism, ed 7. Philadelphia, Lippincott Williams and Wilkins, 2008.
29.
Marx SJ, Simonds WF: Hereditary hormone excess: genes, molecular pathways, and syndromes. Endocr Rev 2005;26:615–661.
30.
Crabtree JS, Scacheri PC, Ward JM, Garrett-Beal L, Emmert-Buck MR, Edgemon KA, Lorang D, Libutti SK, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS: A mouse model of MEN1 develops multiple endocrine tumors. Proc Natl Acad Sci USA 2001;98:1118–1123.
31.
Crabtree JS, Scacheri PC, Ward JM, McNally SR, Swain GP, Montagna C, Hager JH, Hanahan D, Edlund H, Magnuson MA, Garrett-Beal L, Burns AL, Ried T, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS: Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol Cell Biol 2003;23:6075–6085.
32.
Loffler KA, Biondi CA, Gartside M, Waring P, Stark M, Serewko-Auret MM, Muller HK, Hayward NK, Kay GF: Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1. Int J Cancer 2006;120:259–267.
33.
Anlauf M, Perren A, Meyer CL, Schmid S, Saremaslani P, Kruse ML, Weihe E, Komminoth P, Heitz PU, Klöppel G: Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas. Gastroenterology 2005;128:1187–1198.
34.
Ratliff JK, Oldfield EH: Multiple pituitary adenomas in Cushing’s disease. J Neurosurg 2000;93:753–761.
35.
Jastania RA, Alsaad KO, Al-Shraim M, Kovacs K, Asa SL: Double adenomas of the pituitary: transcription factors Pit-1, T-pit, and SF-1 identify cytogenesis and differentiation. Endocr Pathol 2005;16:187–194.
36.
Al Brahim NY, Rambaldini G, Ezzat S, Asa SL: Complex endocrinopathies in MEN-1:diagnostic dilemmas in endocrine oncology. Endocr Pathol 2007;18:37–41.
37.
Mooi WJ, Peeper DS: Oncogene-induced cell senescence – halting on the road to cancer. N Engl J Med 2006;355:1037–1046.
38.
Lamers CB, Froeling PG: Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis type I (MEA I). Am J Med 1979;66:422–424.
39.
Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem MC, Assayag M, Peix JL, Pugeat M, Rohmer V, Vallotton M, Lenoir G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A, Calender A: Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 1997;63:455–467.
40.
Stratakis CA, Schussheim DH, Freedman SM, Keil MF, Pack SD, Agarwal SK, Skarulis MC, Weil RJ, Lubensky IA, Zhuang Z, Oldfield EH, Marx SJ: Pituitary macroadenoma in a 5 year old: an early expression of MEN1. J Clin Endocrinol Metab 2000;85:4776–4780.
41.
Bai F, Pei X-H, Nishikawa T, Smith MD, Xiong Y: p18Ink-4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. Mol Cell Biol 2007;27:1495–1504.
42.
Loffler KA, Biondi CA, Gartside MG, Serewko-Auret MM, Duncan R, Tonks ID, Mould AW, Waring P, Muller HK, Kay GF, Hayward NK: Lack of augmentation of tumor spectrum or severity in dual heterozygous Men1 and Rb1 knockout mice. Oncogene 2007;26:4009–4017.
43.
Matoso A, Zhou Z, Hayama R, Flesken-Nikitin A, Nikitin AY: Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia. Carcinogenesis 2008;29:620–628.
44.
Korsisaari N, Ross J, Wu X, Kowanetz M, Pal N, Hall L, Eastham-Anderson J, Forrest WF, Van Bruggen N, Peale FV, Ferrara N: Blocking vascular endothelial growth factor-A inhibits the growth of pituitary adenomas and lowers serum prolactin levels in a mouse model of multiple endocrine neoplasia type 1. Cancer Res 2008;14:249–258.
45.
Bertolino P, Tong WM, Herrera PL, Casse H, Zhang CX, Wang ZQ: Pancreatic beta cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res 2003;63:4836–4841.
46.
Zhuang Z, Ezzat SZ, Vortmeyer AO, Weil R, Oldfield EH, Park WS, Pack S, Huang S, Agarwal SK, Guru SC, Manickam P, Debelenko LV, Kester MB, Olufemi SE, Heppner C, Crabtree JS, Burns AL, Spiegel AM, Marx SJ, Chandrasekharappa SC, Collins FS, Emmert-Buck MR, Liotta LA, Asa SL, Lubensky IA: Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer Res 1997;57:5446–5451.
47.
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.
48.
Agarwal SK, Scacheri PC, Rice TS, Kennedy PA, Ozawa A, Burgess-Hickman A, Popson, SA, Burns AL, Mateo C, Simonds WF, Oliver B, Libutti SK, Novotny EA, Halawi MJ, Ji Y, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ: MEN1 gene: mutation and pathophysiology. Ann Endocrinol (Paris) 2006;67(suppl 4):1S12–1S13.
49.
Agarwal SK, Novotny EA, Crabtree JS, Weitzman JB, Yaniv M, Burns AL, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ: Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc Natl Acad Sci USA 2003;100:10770–10775.
50.
Ozanne BW, Spence HJ, McGarry LC, Hennigan RF: Transcription factors control invasion: AP-1 the first among equals. Oncogene 2007;26:1–10.
51.
Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA, Gibbs D, Hua X, Roeder RG, Meyerson M, Hess JL: Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci USA 2005;102:749–754.
52.
Karnik SK, Hughes CM, Gu XY, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK: Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27(Kip1) and p18(INK4c). Proc Natl Acad Sci USA 2005;102:14659–14664.
53.
Yokoyama A, Somervaille TCP, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML: The menin tumor suppressor protein is an essential oncogenic cofactor for MLL- associated leukemogenesis. Cell 2005;123:207–218.
54.
Karnik SK, Chen HN, McLean GW, Heit JJ, Gu X, Zhang AY, Fontaine M, Yen MH, Kim SK: Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science 2007;318:806–809.
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