Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

// Kati Kämpjärvi 1, * , Tiina M. Järvinen 2, * , Tuomas Heikkinen 1 , Amy S. Ruppert 3 , Leigha Senter 2 , Kevin W. Hoag 2 , Olli Dufva 1 , Mika Kontro 4 , Laura Rassenti 5 , Erin Hertlein 3 , Thomas J. Kipps 5 , Kimmo Porkka 4 , John C. Byrd 3 , Albert de la Chapelle 2 , Pia Vahteristo 1 1 Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland 2 Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA 3 Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA 4 Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland 5 Moores University of California-San Diego Cancer Center, University of California San Diego, CA, USA * These authors have contributed equally to this work Correspondence to: Pia Vahteristo, e-mail: pia.vahteristo@helsinki.fi Keywords: Chronic lymphocytic leukemia, MED12, somatic mutation, cancer genetics, prognosis Received: October 01, 2014      Accepted: November 15, 2014      Published: February 24, 2015 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.