title: Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas.
abstract: BACKGROUND
  Insulinomas represent pancreatic neuroendocrine neoplasms that cause severe morbidity attributed to their often pronounced endocrine activity. Apart from hereditary forms such as multiple endocrine neoplasia type 1 (MEN-1), genetic causes for sporadic insulinoma development had remained obscure until recently. Applying next-generation sequencing methods, disease-causing genetic alterations have been identified in various endocrine tumors.
  
  
  OBJECTIVE
  Paired tumor and blood DNA from eight patients with sporadic insulinomas (five females and two malignant tumors) were analyzed by whole-exome sequencing. After this initial analysis, Ying Yang 1 (YY1) mutation status was assessed in a larger cohort of 39 additional insulinomas (including eight malignant and one liver metastasis) from three German hospitals by targeted sequencing. The mutation status was correlated with various clinical parameters.
  
  
  RESULTS
  A range of one to 12 somatic genetic variants were identified by exome sequencing. A recurrent somatic Thr372Arg YY1 point mutation was detected in two patients of the initial cohort and four patients of the second cohort (total, six of 47; 13%). The presence of the mutation was associated with a trend toward higher age (63.5 y; IQR, 48.0-74.0 vs 45.0 y; IQR, 33.0-63.0; P = .05), and all affected patients were females (six of six; P = .04). All other clinical parameters, including the presence of malignancy and metastatic spread, tumor localization, and hypoglycemic episodes were not different between YY1-mutated and nonmutated tumor carriers.
  
  
  CONCLUSIONS
  The somatic Thr372Arg YY1 mutation is a relevant finding in female patients with sporadic insulinomas. The prevalence of this mutation in this Caucasian population is considerably lower compared to that of a recently described Asian cohort.
authors.affiliation: Medizinische Klinik und Poliklinik IV (U.D.L., G.D.D., M.R., F.B.), Klinikum der Universität München, 80336 Munich, Germany; Department of Visceral, Thoracic, and Vascular Surgery (E.P.S., D.W., D.K.B.), University Hospital Giessen and Marburg GmbH, 35043 Marburg, Germany; Institute of Human Genetics (T.W., A.S., T.S., S.D., T.M., T.M.S.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Funktionsbereich Spezielle Endokrinologie (A.K., M.S.), Universitätsklinikum Düsseldorf, 40225 Düsseldorf Germany; Biobank (under the administration of the Human Tissue and Cell Research) Foundation (W.E.T.), Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany; Germany Institute of Human Genetics (T.M., T.M.S.), Technische Universität München, 81675 Munich, Germany; German Centre for Cardiovascular Research Partner Site (T.M., T.M.S.), Munich Heart Alliance, 80802 Munich, Germany; Department of Medicine I (M.F.), Endocrine and Diabetes Unit, University Hospital, University of Würzburg, 97080 Würzburg, Germany; and Comprehensive Cancer Center Mainfranken (M.F.), University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Urs D
authors.initials: UD
authors.lastname: Lichtenauer
authors.forename: Guido
authors.initials: G
authors.lastname: Di Dalmazi
authors.forename: Emily P
authors.initials: EP
authors.lastname: Slater
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Anne
authors.initials: A
authors.lastname: Kuebart
authors.forename: Anett
authors.initials: A
authors.lastname: Schmittfull
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.forename: Susanne
authors.initials: S
authors.lastname: Diener
authors.forename: Dominik
authors.initials: D
authors.lastname: Wiese
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Schott
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000328:Adult; D000368:Aged; D059472:Exome; D005260:Female; D006801:Humans; D007340:Insulinoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D050986:YY1 Transcription Factor / Q000235:genetics*
chemical_list: D050986:YY1 Transcription Factor; C494698:YY1 protein, human