A Validated Gene Expression Signature of High Risk Multiple Myeloma Is Defined by Deregulated Expression of Genes Mapping to Chromosome 1.

In an effort to better define the molecular mechanisms of aggressiveness in multiple myeloma (MM), we performed microarray analysis on tumor cells from 532 newly diagnosed patients treated on two separate protocols. We hypothesized that expression extremes of a subset of genes linked to poor survival might point to important regions of the genome that when amplified or deleted may lead to altered expression of resident genes and hence disease progression. Using log rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P <.001) were linked to early disease-related death. Importantly, the majority of up-regulated genes mapped to 1q and down-regulated genes mapped to 1p. This high-risk signature, seen in 13% of patients, was linked to poor outcome in both a training (HR 5.16, P <.0001) and test cohort (HR 4.96, P <.0001) and was an independent predictor of outcome in multivariate analysis (P <.0001) that included the ISS. Using a combination of high-resolution aCGH and microarray profiling, we recently identified 47 minimal common regions (MCRs) of genomic gain across the myeloma genome and 207 genes in these MCRs whose expression increases with copy number changes (Carrasco et al., Cancer Cell 2006 9:313–325). When the expression of these copy number-sensitive genes was compared between the high and low risk diseases defined by the 70 gene model, we found that only genes mapping to MCRs at 1q21, 1q22 and 1q43–q44 were significantly over expressed in high-risk disease. These data support prior studies indicating that gains of 1q and amplification of 1q21 and loss of 1p define a distinct subset of disease with poor survival. Novel treatment modalities are justified in these high-risk patients who have not yet benefited from advances in MM therapy.