Journal of Endocrinological Investigation

, Volume 27, Issue 11, pp 1015–1021 | Cite as

Novel somatic MEN1 gene alterations in sporadic primary hyperparathyroidism and correlation with clinical characteristics

  • D. Scarpelli
  • L. D’Aloiso
  • F. Arturi
  • A. Scillitani
  • I. Presta
  • M. Bisceglia
  • C. Cristofaro
  • D. Russo
  • S. Filetti
Original Article


Primary hyperparathyroidism (pHPT) is a common endocrine disease that in more than 95% of cases is sporadic and only in some cases is caused by inherited disorders, isolated or as part of multiple endocrine neoplasia (MEN1 and 2). Somatic mutations of MEN1 gene have also been described in sporadic parathyroid tumors. In our study, we examined the presence of alterations in MEN1 gene in a series of 39 patients who had undergone surgery for sporadic pHPT (35 with parathyroid adenoma or hyperplasia, 4 with a carcinoma). A genotype-phenotype correlation was also analysed. After DNA extraction from paraffin-embedded tissues, we amplified by PCR and sequenced the exons 2–10 of the MEN1 gene. Somatic MEN1 mutations were detected in 6 of the 35 patients with a benign parathyroid lesion examined (17.1%), whereas no alterations were found in the carcinomas. Four novel MEN1 gene mutations were identified as follows: one frameshift mutation (222insT, exon 2), one frameshift deletion (912delTA, exon 5), one in-frame deletion (835del18, exon 4) and one missense mutation (P291A, exon 6). In addition, one missense mutation (L89R, exon 2) and one nonsense mutation (Q536X, exon 10) were previously reported. Moreover, two polymorphisms were also found: one allele carried a R171Q polymorphism (1/39 tumors), while a D418D polymorphism (GAC/GAT) was found in 15 and 8 tumors in hetero (CT) and homozygosity (TT), respectively. In no case (mutations and/or polymorphisms) did we find a genotype-phenotype correlation. In conclusion, our data demonstrate the presence of somatic alterations of the MEN1 tumor suppressor gene in about one fifth of benign sporadic parathyroid tumors. The absence of a genotype-phenotype correlation, however, suggests the involvement of other genetic/epigenetic factors for the full expression of the disease.


Non-familial primary hyperparathyroidism multiple endocrine neoplasia type 1 (MEN 1) mutation analysis MEN 1 gene menin 


  1. 1.
    Bilezikian JP, Silverberg S, Gartenberg F, et al. Clinical presentation of primary hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA eds. The parathyroids: basic and clinical concepts. New York: Raven Press. 1994, 457.Google Scholar
  2. 2.
    Heath H 3rd, Hodgson SF, Kennedy MA. Primary hyperparathyroidism: incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980, 302: 189–93.PubMedCrossRefGoogle Scholar
  3. 3.
    Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000, 343: 1863–75.PubMedCrossRefGoogle Scholar
  4. 4.
    Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia type 1. Science 1997, 276: 404–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Guru SC, Goldsmith PK, Burns Al, et al. Menin, The product of the MEN1 gene, is a nuclear protein. Proc Nat Acad Sci USA 1998, 95: 1630–4.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    The European Consortium on MEN1: Belgium: Lemmens I, Van de Ven WJ, Kas K, et al. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Hum Mol Genet 1997, 6: 1177–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Agarwal SK, Kester MB, Debelenko LV, et al. Germline Mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997, 6: 1169–75.PubMedCrossRefGoogle Scholar
  8. 8.
    Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Gen 1997, 16: 375–8.CrossRefGoogle Scholar
  9. 9.
    Carling T, Correa P, Hessman O, et al. Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab 1998, 83: 2960–3.PubMedGoogle Scholar
  10. 10.
    Farnebo F, Teh BT, Kytola S, et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 1998, 83: 2627–30.PubMedGoogle Scholar
  11. 11.
    Sato K, Yamazaki K, Zhu H, et al. Somatic mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in patients with sporadic, nonfamilial primary hyperparathyroidism. Surgery 2000, 127: 337–41.PubMedCrossRefGoogle Scholar
  12. 12.
    Cetani F, Pardi E, Vignali E, et al. MEN1 gene alterations do not correlate with the phenotype of sporadic primary hyperparathyroidism. J Endocrinol Invest 2002, 25: 508–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Pannett AA, Kennedy AM, Turner JJ, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf) 2003, 58: 639–46.CrossRefGoogle Scholar
  14. 14.
    Thakker RV, Bouloux P, Wooding C, et al. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 1989, 321: 218–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Bystrom C, Larsson C, Blomberg C, et al. Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Proc Nat Acad Sci USA 1990, 87: 1968–72.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Friedman E, De Marco L, Gejman PV, et al. Allelic loss from chromosome 11 in parathyroid tumors. Cancer Res 1992, 52: 6804–9.PubMedGoogle Scholar
  17. 17.
    Bassett JH, Forbes SA, Pannett AA, et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998, 62: 232–44.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Dwight T, Nelson AE, Theodosopoulos G, et al. Independent genetic events associated with the development of multiple parathyroid tumors in patients with primary hyperparathyroidism. Am J Pathol 2002, 161: 1299–306.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 1989, 83: 2034–40.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/ PRAD1 expression in parathyroid adenomas: an immu-nohistochemical study. J Clin Endocrinol Metab 1996, 81: 1736–9.PubMedGoogle Scholar
  21. 21.
    Vasef MA, Brynes RK, Sturm M, Bromley C, Robinson RA. Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod Pathol 1999 12: 412–6.PubMedGoogle Scholar
  22. 22.
    Cryns VL, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 1994, 330: 757–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Dotzenrath C, The BT, Farnebo F, et al. Allelic loss of the retinoblastoma tumor suppressor gene: a marker for aggressive parathyroid tumors? J Clin Endocrinol Metab 1996, 81: 3194–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999, 96: 143–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaji H, Canaff L, Lebrun JJ, Goltzman D, Hendy GN. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling. Proc Nat Acad Sci USA 2001, 98: 3837–42.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Ohkura N, Kishi M, Tsukada T, Yamaguchi K. Menin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis suppressor nm23. Biochem Biophys Res Commun 2001, 282: 1206–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Heppner C, Bilimoria KY, Agarwal SK, et al. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. Oncogene 2001, 20: 4917–25.PubMedCrossRefGoogle Scholar
  28. 28.
    Schussheim DH, Skarulis MC, Agarwal SK, et al. Multiple endocrine neoplasia type 1: new clinical and basic findings. Trend Endocrinol Metab 2001, 12: 173–8.CrossRefGoogle Scholar
  29. 29.
    Shimizu S, Tsukada T, Futami H, et al. Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1. Jpn J Cancer Res 1997, 88: 1029–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Marx S, Spiegel, AM, Skarulis MC, Doppman JL, Collins FS, Lotta LA. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998, 129: 484–94.PubMedCrossRefGoogle Scholar
  31. 31.
    Knudson AG JR. Mutation and cancer: statistical study of retinoblastoma. Proc Nat Acad Sci USA 1971, 68: 820–3.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Nat Acad Sci USA 2001, 98: 1118–23.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Shan L, Nakamura Y, Nakamura M, et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest 1998, 78: 471–5.PubMedGoogle Scholar
  34. 34.
    Howell, VM, Haven CJ, Kahnoski K, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 2003, 40: 657–63.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Shattuck TM, Valimaki, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003, 349: 1722–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Edstrom E, Mahlamaki E, Nord B, et al. Comparative genomic hybridization reveals frequent losses of chromosomes 1p and 3q in pheochromocytomas and abdominal paragangliomas, suggesting a common genetic etiology. Am J Pathol 2000, 156: 651–9.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Correa P, Lundgren E, Rastad J, Akerstrom G, Westin G, Carling T. Multiple endocrine neoplasia type 1 polymorphism D418D is associated with sporadic primary hyper-parathyroidism. Surgery 2002, 132: 450–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Teh, BT, Kytölä S, Farnebo F, et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 1998, 83: 2621–6.PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2004

Authors and Affiliations

  • D. Scarpelli
    • 1
  • L. D’Aloiso
    • 2
  • F. Arturi
    • 1
  • A. Scillitani
    • 2
  • I. Presta
    • 1
  • M. Bisceglia
    • 2
  • C. Cristofaro
    • 1
  • D. Russo
    • 1
  • S. Filetti
    • 3
  1. 1.Department of Clinical and Experimental Medicine “G. Salvatore” and Department of Pharmacobiological SciencesUniversity “Magna Graecia” of CatanzaroCatanzaroItaly
  2. 2.Unit of EndocrinologyIRCCS, Casa Sollievo della SofferenzaS. Giovanni Rotondo, FoggiaItaly
  3. 3.Department of Clinical SciencesUniversity of Rome “La Sapienza”RomaItaly

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