title: The molecular classification of multiple myeloma.
abstract: To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
authors.affiliation: Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.forename: James P
authors.initials: JP
authors.lastname: Stewart
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hanamura
authors.forename: Sushil
authors.initials: S
authors.lastname: Gupta
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sawyer
authors.forename: Bart
authors.initials: B
authors.lastname: Burington
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Klaus
authors.initials: K
authors.lastname: Hollmig
authors.forename: Mauricio
authors.initials: M
authors.lastname: Pineda-Roman
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Ronald
authors.initials: R
authors.lastname: Walker
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zangari
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
mesh_terms: D002874:Chromosome Mapping; D016000:Cluster Analysis; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics; D003627:Data Interpretation, Statistical; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D009101:Multiple Myeloma / Q000145:classification* / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D010950:Plasma Cells / Q000276:immunology; D011379:Prognosis; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D053668:Syndecan-1; D053667:Syndecans
chemical_list: D056741:Cyclin D; D016213:Cyclins; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C508241:SDC1 protein, human; D053668:Syndecan-1; D053667:Syndecans