title: Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. We performed systematic database search and identified highly specific MED12 mutations in CLL patients. To study this further, we collected three independent sample series comprising over 700 CLL samples and screened MED12 exons 1 and 2 by direct sequencing. Mutations were identified at significant frequency in all three series with a combined mutation frequency of 5.2% (37/709). Positive mutation status was found to be associated with unmutated IGHV and ZAP70 expression, which are well-known poor prognosis markers in CLL. Our results recognize CLL as the first extrauterine cancer type where 5'terminus of MED12 is mutated at significant frequency. Functional analyses have shown that these mutations lead to dissociation of Cyclin C-CDK8/19 from the core Mediator and to the loss of Mediator-associated CDK kinase activity. Additional studies on the role of MED12 mutation status as a putative prognostic factor as well as mutations' exact tumorigenic mechanism in CLL are warranted.
authors.affiliation: Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kämpjärvi
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Järvinen
authors.affiliation: Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.affiliation: Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Leigha
authors.initials: L
authors.lastname: Senter
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoag
authors.affiliation: Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Dufva
authors.affiliation: Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kontro
authors.affiliation: Moores University of California-San Diego Cancer Center, University of California San Diego, CA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.affiliation: Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Hertlein
authors.affiliation: Moores University of California-San Diego Cancer Center, University of California San Diego, CA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.affiliation: Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex