title: The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma.
abstract: OBJECTIVE
  Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.
  
  
  METHODS
  Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.
  
  
  RESULTS
  In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.
  
  
  CONCLUSIONS
  Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR.
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pawlyn
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kaiser
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heuck
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Murison
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Shweta S
authors.initials: SS
authors.lastname: Chavan
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Dil B
authors.initials: DB
authors.lastname: Begum
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Nasrin M
authors.initials: NM
authors.lastname: Dahir
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paula Z
authors.initials: PZ
authors.lastname: Proszek
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Cairns
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Boyle
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Jones
authors.affiliation: University of Leeds, Leeds, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.affiliation: Clinical Immunology, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.affiliation: St James's University Hospital, Leeds, United Kingdom.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Owen
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Gregory
authors.affiliation: Department of Haematology, Newcastle University, Newcastle, United Kingdom.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: The Institute of Cancer Research, London, United Kingdom. GJMorgan@uams.edu.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D059472:Exome / Q000235:genetics; D005260:Female; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics; D011446:Prospective Studies
chemical_list: D006657:Histones; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase