Avalidated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1

John D. Shaughnessy, Fenghuang Zhan, Bart E. Burington, Yongsheng Huang, Simona Colla, Ichiro Hanamura, James P. Stewart, Bob Kordsmeier, Christopher Randolph, David R. Williams, Yan Xiao, Hongwei Xu, Joshua Epstein, Elias Anaissie, Somashekar G. Krishna, Michele Cottler-Fox, Klaus Hollmig, Abid Mohiuddin, Mauricio Pineda-Roman, Guido TricotFrits Van Rhee, Jeffrey Sawyer, Yazan Alsayed, Ronald Walker, Maurizio Zangari, John Crowley, Bart Barlogie

Research output: Contribution to journalArticle

616 Scopus citations

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 downregulated 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.

Original languageEnglish (US)
Pages (from-to)2276-2284
Number of pages9
JournalBlood
Volume109
Issue number6
DOIs
StatePublished - Mar 15 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Shaughnessy, J. D., Zhan, F., Burington, B. E., Huang, Y., Colla, S., Hanamura, I., Stewart, J. P., Kordsmeier, B., Randolph, C., Williams, D. R., Xiao, Y., Xu, H., Epstein, J., Anaissie, E., Krishna, S. G., Cottler-Fox, M., Hollmig, K., Mohiuddin, A., Pineda-Roman, M., ... Barlogie, B. (2007). Avalidated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood, 109(6), 2276-2284. https://doi.org/10.1182/blood-2006-07-038430