, Volume 15, Issue 1, pp 113–117 | Cite as

Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype

  • Nikolaos PerakakisEmail author
  • Felix Flohr
  • Gian Kayser
  • Oliver Thomusch
  • Lydia Parsons
  • Franck Billmann
  • Ernst von Dobschuetz
  • Susanne Rondot
  • Jochen Seufert
  • Katharina Laubner
Case report


BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant hereditary disorder associated with the development of endocrine tumors due to reduced expression of the tumor suppressor protein menin. Recent studies indicate a general role of menin in carcinogenesis, affecting the prevalence and clinical course of common non-endocrine tumors such as breast cancer, hepatocellular carcinoma and melanoma. Here we report a new germline missense mutation of Men1 in a German family with atypical tumor phenotype over three generations. Based on the type of mutation, we discuss possible changes in menin function leading to atypical tumorigenesis and present the clinical significance of such findings. CASE PRESENTATION: A German family with a history of primary hyperparathyroidism presented to our Hospital for further evaluation. Members of the family demonstrated many different atypical tumors, such as renal cell carcinoma, papillary thyroid cancer and prostate cancer. DNA sequencing from peripheral blood revealed a novel mutation: Ser38Cys [TCC>TGC] in exon 2, codon 38 of Men1. This novel mutation is located in a region of menin which is responsible for interactions with the transcription factor JunD. This factor has recently been associated with prostate cancer. DNA sequencing of two of the atypical tumors (prostate cancer, papillary thyroid cancer) did not reveal a loss of heterozygosity, indicating an impact on menin expression and function in the heterozygous state, in line with results in +/−Men1 mutant mice developing prostate cancer. CONCLUSION: The results and clinical course of disease in this case indicate the potential role of menin in the development of non-endocrine or atypical-endocrine tumors in MEN1 patients. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis. Nevertheless, in families with uncommon manifestations of the syndrome early diagnostic adjustments should be considered.

Key words

Atypical tumors MEN1 New mutation Prostate cancer 


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  1. 1.
    Thakker RV, Newey PJ, Walls GV, et al, 2012 Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97: 2990–3011.CrossRefPubMedGoogle Scholar
  2. 2.
    Koch CA, Pacak K, Chrousos GP, 2002 The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 87: 5367–5384.CrossRefPubMedGoogle Scholar
  3. 3.
    Cavalli T, Giudici F, Nesi G, et al, 2014 Sarcomatoid carcinoma of the kidney in a MEN1 patient: case report and genetic profile. Endocr J 61: 781–787.CrossRefPubMedGoogle Scholar
  4. 4.
    Dreijerink KM, Goudet P, Burgess JR, Valk GD, 2014 Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med 371: 583–584.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gao SB, Feng ZJ, Xu B, et al, 2011 Menin represses malignant phenotypes of melanoma through regulating multiple pathways. J Cell Mol Med 15: 2353–2363.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gao SB, Xu B, Ding LH, et al, 2014 The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma. J Hepatol 61: 832–839.CrossRefPubMedGoogle Scholar
  7. 7.
    Harding B, Lemos MC, Reed AA, et al, 2009 Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer 16: 1313–1327.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ren F, Xu HW, Hu Y, et al, 2012 Expression and subcellular localization of menin in human cancer cells. Exp Ther Med 3: 1087–1091.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yang YQ, Qi J, Xu JQ, Hao P, 2014 MicroRNA-142-3p, a novel target of tumor suppressor menin, inhibits osteosarcoma cell proliferation by down-regulation of FASN. Tumour Biol 35: 10287–10293.CrossRefPubMedGoogle Scholar
  10. 10.
    Fang M, Xia F, Mahalingam M, Virbasius CM, Wajapeyee N, Green MR, 2013 MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. Mol Cell Biol 33: 2635–2647.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Seigne C, Fontaniere S, Carreira C, et al, 2010 Characterisation of prostate cancer lesions in heterozygous Menl mutant mice. BMC Cancer 10: 395.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Manson-Bahr D, Ball R, Gundem G, et al, 2015 Mutation detection in formalin-fixed prostate cancer biopsies taken at the time of diagnosis using next-generation DNA sequencing. J Clin Pathol 68: 212–217.CrossRefPubMedGoogle Scholar
  13. 13.
    Dilley WG, Kalyanaraman S, Verma S, Cobb JP, Laramie JM, Lairmore TC, 2005 Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome. Mol Cancer 4: 9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Brennan P, 2015 Breast cancer risk in MEN1 — a cancer genetics perspective. Clin Endocrinol (Oxf) 82: 327–329.CrossRefGoogle Scholar
  15. 15.
    Dreijerink KM, Valk GD, 2015 Reply to: Breast cancer risk in MEN1 — a cancer genetics perspective. Clin Endocrinol (Oxf) 83: 141.CrossRefGoogle Scholar
  16. 16.
    Lemos MC, Thakker RV, 2008 Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 29: 22–32.CrossRefPubMedGoogle Scholar
  17. 17.
    Bartsch DK, Slater EP, Albers M, et al, 2014 Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain. J Clin Endocrinol Metab 99: E2387–291.CrossRefPubMedGoogle Scholar
  18. 18.
    Thevenon J, Bourredjem A, Faivre L, et al, 2013 Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d’etude des Tumeurs Endocrines (GTE) cohort study. Hum Mol Genet 22: 1940–1948.CrossRefPubMedGoogle Scholar
  19. 19.
    Mehraein-Ghomi F, Kegel SJ, Church DR, et al, 2014 Targeting androgen receptor and JunD interaction for prevention of prostate cancer progression. Prostate 74: 792–803.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Desai D, McPherson LA, Higgins JP, Weigel RJ, 2001 Genetic analysis of a papillary thyroid carcinoma in a patient with MEN1. Ann Surg Oncol 8: 342–346.CrossRefPubMedGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2016

Authors and Affiliations

  • Nikolaos Perakakis
    • 1
    Email author
  • Felix Flohr
    • 2
  • Gian Kayser
    • 3
  • Oliver Thomusch
    • 4
  • Lydia Parsons
    • 1
    • 5
  • Franck Billmann
    • 4
  • Ernst von Dobschuetz
    • 6
  • Susanne Rondot
    • 7
  • Jochen Seufert
    • 1
  • Katharina Laubner
    • 1
  1. 1.Division of Endocrinology and Diabetology, Department of Internal Medicine IIUniversity Hospital of FreiburgFreiburgGermany
  2. 2.Department of Internal Medicine ISt. Vincentius-HospitalKarlsruheGermany
  3. 3.Department of Pathology, Institute of Surgical PathologyUniversity Hospital of FreiburgFreiburgGermany
  4. 4.Division of Endocrine Surgery, Department of General and Visceral SurgeryUniversity Hospital of FreiburgFreiburgGermany
  5. 5.School of BiosciencesCardiff UniversityCardiffUK
  6. 6.Division of Endocrine SurgeryHospital Reinbek St. Adolf-Stift ReinbekReinbekGermany
  7. 7.Endocrine Practice and Molecular LaboratoryHeidelbergGermany

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