title: Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations.
abstract: BACKGROUND
  Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease.
  
  
  OBJECTIVE
  The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations.
  
  
  METHODS
  Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected. All exons of the GCGR gene were analyzed for mutations by Sanger and next-generation sequencing. Genotyping for all detected GCGR variants was performed in 2560 healthy individuals.
  
  
  METHODS
  Six patients with GCA, and the parents of one patient were included in the study.
  
  
  METHODS
  The main outcome measures were the correlations between the patients' GCGR mutation status and the respective clinicopathological data.
  
  
  RESULTS
  GCGR germline mutations were found in three of six patients. Patient 1 harbored a homozygous stop mutation. This patient's parents showed an identical but heterozygous GCGR mutation. Patient 2 had two different heterozygous point mutations leading each to premature stop codons. Patient 3 exhibited two homozygous missense mutations. No GCGR mutations were identified in the three other patients and in a large cohort of healthy subjects. The patients harboring GCGR mutations exhibited a greater number of tumors and larger tumors than patients with wild-type GCGR. One of the patients with wild-type GCGR showed lymph node micrometastases.
  
  
  CONCLUSIONS
  GCA with GCGR germline mutations seems to follow an autosomal-recessive trait. By interrupting the GCGR signaling pathways GCGR mutations probably cause GCA via glucagon cell hyperplasia. GCA also occurs in patients without GCGR mutations, but seems to be associated with fewer and smaller tumors.
authors.affiliation: Department of Pathology (B.S., J.S., M.H.), University of Tübingen, 72076 Germany; Institute of Pathology (M.A.), Limburg, 65549 Germany; Institute of Pathology (T.H.), Traunstein, 83278 Germany; POPGEN Biobank Project (S.B.), Christian-Albrechts-University, Kiel, 24105 Germany; First Department of Internal Medicine (J.H.), University Hospital, Dresden, 01304 Germany; Department of Clinical Pathology (A.W.), University Hospital Zürich, 8091 Switzerland; Service de Gastroentérologie-Pancréatologie (P.H.), Hôpital Beaujon, Clichy La Garenne, 92110 France; Department of Pathology (A.C.), Hôpital Bichat, Paris, 75018 France; Institute of Pathology (W.H.), Hospital Wels-Grieskirchen, Wels, 4600 Austria; Institute of Epidemiology and Biobank POPGEN (W.L.), Christian-Albrechts-University, 24105 Kiel, Germany; LKC Medicine (B.O.B.), Nanyang Technological University, 639798 Singapore and Imperial College London, London WC1E 6BT, UK and Department of Internal Medicine I, University of Ulm Medical Centre, Ulm, 89081 Germany; and Department of Pathology (G.K.), Technical University München, 80333 Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Jan
authors.initials: J
authors.lastname: Sperveslage
authors.forename: Martin
authors.initials: M
authors.lastname: Anlauf
authors.forename: Maike
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: Tobias
authors.initials: T
authors.lastname: Henopp
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.forename: Walter
authors.initials: W
authors.lastname: Höbling
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005934:Glucagon; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018027:Receptors, Glucagon / Q000235:genetics*
chemical_list: D018027:Receptors, Glucagon; D005934:Glucagon