title: A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.
abstract: To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.
authors.affiliation: Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. shaughnessyjohn@uams.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Bart E
authors.initials: BE
authors.lastname: Burington
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hanamura
authors.forename: James P
authors.initials: JP
authors.lastname: Stewart
authors.forename: Bob
authors.initials: B
authors.lastname: Kordsmeier
authors.forename: Christopher
authors.initials: C
authors.lastname: Randolph
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xu
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Somashekar G
authors.initials: SG
authors.lastname: Krishna
authors.forename: Michele
authors.initials: M
authors.lastname: Cottler-Fox
authors.forename: Klaus
authors.initials: K
authors.lastname: Hollmig
authors.forename: Abid
authors.initials: A
authors.lastname: Mohiuddin
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: Jeffrey
authors.initials: J
authors.lastname: Sawyer
authors.forename: Yazan
authors.initials: Y
authors.lastname: Alsayed
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
mesh_terms: D000368:Aged; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008957:Models, Genetic; D005810:Multigene Family; D009101:Multiple Myeloma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D012008:Recurrence; D012307:Risk Factors; D015996:Survival Rate