title: Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Perakakis
authors.affiliation: Department of Internal Medicine I, St. Vincentius-Hospital, Karlsruhe, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Flohr
authors.affiliation: Department of Pathology, Institute of Surgical Pathology, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Gian
authors.initials: G
authors.lastname: Kayser
authors.affiliation: Division of Endocrine Surgery, Department of General and Visceral Surgery, University Hospital of Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Thomusch
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany,School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Lydia
authors.initials: L
authors.lastname: Parsons
authors.affiliation: Division of Endocrine Surgery, Department of General and Visceral Surgery, University Hospital of Freiburg, Germany.
authors.forename: Franck
authors.initials: F
authors.lastname: Billmann
authors.affiliation: Division of Endocrine Surgery Hospital Reinbek St. Adolf-Stift Reinbek, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: von Dobschuetz
authors.affiliation: Endocrine Practice and Molecular Laboratory, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rondot
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Seufert
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Laubner
mesh_terms: D000368:Aged; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins