title: MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas.
abstract: Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis.
  
  
  
  MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA).
  
  
  
  Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours.
  
  
  
  Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours.
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kämpjärvi
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Netta
authors.initials: N
authors.lastname: Mäkinen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Miika
authors.initials: M
authors.lastname: Mehine
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Salla
authors.initials: S
authors.lastname: Välipakka
authors.affiliation: Department of Obstetrics and Gynecology, Oulu University Hospital, PEDEGO Research Unit, University of Oulu, FIN-90220 Oulu, Finland.|Medical Research Center Oulu, FIN-90220 Oulu, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Uimari
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Hanna-Riikka
authors.initials: HR
authors.lastname: Heinonen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Tolvanen
authors.affiliation: Medical Research Center Oulu, FIN-90220 Oulu, Finland.|Department of Pathology, Oulu University Hospital, Cancer and Translational Medicine Research Unit, University of Oulu, FIN-90220 Oulu, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Ahtikoski
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland.|Department of Biochemistry and Developmental Biology, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Nanna
authors.initials: N
authors.lastname: Sarvilinna
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Sjöberg
authors.affiliation: Department of Pathology, The Laboratory of Helsinki University Central Hospital (HUSLAB), Helsinki University Central Hospital and Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Biosciences and Nutrition, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D005649:Fumarate Hydratase / Q000378:metabolism*; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007889:Leiomyoma / Q000201:enzymology* / Q000235:genetics*; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D059467:Transcriptome; D014594:Uterine Neoplasms / Q000201:enzymology* / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C460107:MED12 protein, human; D056892:Mediator Complex; D005649:Fumarate Hydratase