title: Recurrent CDKN1B (p27) mutations in hairy cell leukemia.
abstract: Hairy cell leukemia (HCL) is marked by near 100% mutational frequency of BRAFV600E mutations. Recurrent cooperating genetic events that may contribute to HCL pathogenesis or affect the clinical course of HCL are currently not described. Therefore, we performed whole exome sequencing to explore the mutational landscape of purine analog refractory HCL. In addition to the disease-defining BRAFV600E mutations, we identified mutations in EZH2, ARID1A, and recurrent inactivating mutations of the cell cycle inhibitor CDKN1B (p27). Targeted deep sequencing of CDKN1B in a larger cohort of HCL patients identify deleterious CDKN1B mutations in 16% of patients with HCL (n = 13 of 81). In 11 of 13 patients the CDKN1B mutation was clonal, implying an early role of CDKN1B mutations in the pathogenesis of HCL. CDKN1B mutations were not found to impact clinical characteristics or outcome in this cohort. These data identify HCL as having the highest frequency of CDKN1B mutations among cancers and identify CDNK1B as the second most common mutated gene in HCL. Moreover, given the known function of CDNK1B, these data suggest a novel role for alterations in regulation of cell cycle and senescence in HCL with CDKN1B mutations.
authors.affiliation: Department of Medicine V, University Hospital Heidelberg, Genome Biology Unit, European Molecular Biology Laboratory, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hüllein
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Stanley Chun-Wei
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Centre for Molecular Pathology, Royal Marsden NHS Foundation Trust, London, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Ernest and Helen Scott Hematological Research Institute, University of Leicester, Leicester, United Kingdom;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jayne
authors.affiliation: Ernest and Helen Scott Hematological Research Institute, University of Leicester, Leicester, United Kingdom;
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, and.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Oleś
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Monica
authors.initials: M
authors.lastname: Else
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Xiyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Mikołaj
authors.initials: M
authors.lastname: Słabicki
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Bian
authors.initials: B
authors.lastname: Wu
authors.affiliation: Laboratoire d'Hématologie, CHU Côte de Nacre, Caen, France;
authors.forename: Xavier
authors.initials: X
authors.lastname: Troussard
authors.affiliation: Department of Hematology, University Hospital, Essen, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
authors.affiliation: Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany;
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.affiliation: Royal Marsden Hospital, London, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Granzow
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Meggendorfer
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Department of Medicine V, University Hospital Heidelberg.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Richter
authors.affiliation: Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Royal Marsden Hospital, London, United Kingdom;
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel Wahab
authors.affiliation: Department of Medicine V, University Hospital Heidelberg, Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
mesh_terms: D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D004252:DNA Mutational Analysis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000235:genetics*; D009154:Mutation; D012008:Recurrence
chemical_list: C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27