TY - JOUR
T1 - Avalidated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1
AU - Shaughnessy, John D.
AU - Zhan, Fenghuang
AU - Burington, Bart E.
AU - Huang, Yongsheng
AU - Colla, Simona
AU - Hanamura, Ichiro
AU - Stewart, James P.
AU - Kordsmeier, Bob
AU - Randolph, Christopher
AU - Williams, David R.
AU - Xiao, Yan
AU - Xu, Hongwei
AU - Epstein, Joshua
AU - Anaissie, Elias
AU - Krishna, Somashekar G.
AU - Cottler-Fox, Michele
AU - Hollmig, Klaus
AU - Mohiuddin, Abid
AU - Pineda-Roman, Mauricio
AU - Tricot, Guido
AU - Van Rhee, Frits
AU - Sawyer, Jeffrey
AU - Alsayed, Yazan
AU - Walker, Ronald
AU - Zangari, Maurizio
AU - Crowley, John
AU - Barlogie, Bart
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33947217497&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-07-038430
DO - 10.1182/blood-2006-07-038430
M3 - Article
C2 - 17105813
AN - SCOPUS:33947217497
SN - 0006-4971
VL - 109
SP - 2276
EP - 2284
JO - Blood
JF - Blood
IS - 6
ER -