title: Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations.
abstract: The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly.
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pawlyn
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Alex
authors.initials: A
authors.lastname: Murison
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom; Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy;
authors.forename: Annamaria
authors.initials: A
authors.lastname: Brioli
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom; Service des Maladies du Sang, Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, France;
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Boyle
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kaiser
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Dil B
authors.initials: DB
authors.lastname: Begum
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Nasrin B
authors.initials: NB
authors.lastname: Dahir
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Paula
authors.initials: P
authors.lastname: Proszek
authors.affiliation: Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom;
authors.forename: Walter M
authors.initials: WM
authors.lastname: Gregory
authors.affiliation: Clinical Immunology Service, University of Birmingham Medical School, Birmingham, United Kingdom;
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.affiliation: Haematology Department, University of Newcastle, Newcastle-upon-Tyne, United Kingdom; and.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, United Kingdom.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D002885:Chromosomes, Human, Pair 16; D002890:Chromosomes, Human, Pair 20; D002894:Chromosomes, Human, Pair 4; D020732:Cytogenetic Analysis; D004171:Diploidy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000276:immunology; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D011379:Prognosis; D015398:Signal Transduction; D059010:Single-Cell Analysis; D016019:Survival Analysis; D014178:Translocation, Genetic
chemical_list: D007143:Immunoglobulin Heavy Chains