Evolution of Genomic Changes and Their Significance in Myeloma.

Abstract 605

Despite therapeutic advances and high response rates, most if not all patients with multiple myeloma (MM) develop drug resistance and relapse and curative outcomes remain elusive. A prominent feature of MM is striking genomic instability that evolves with the progression of disease. This genomic instability is considered responsible for development of aggressive phenotype associated with relapsed disease and for development of drug resistance. The molecular basis for the generation of this genetic diversity in cancer cells thus has important implication in understanding cancer progression and therapy. However the genomic evolution in MM patient samples has not been documented. Here, we have utilized single nucleotide polymorphism (SNP) arrays to monitor genome-wide changes in heterozygosity and copy number, in two CD138+ MM cell samples collected 6 months apart from 14 MM patients. Genomic changes acquired in the late tumor samples were identified using early samples as baseline. We defined an event as detectable change in heterozygosity/copy number in three or more consecutive SNPs. All 14 MM patients acquired new genomic change in the later sample at a frequency ranging from 0.021 - 2.674 % (i.e. per 100 informative loci investigated). Although the rate of mutation varied, 12 out of 14 patients had acquired >100 mutational events. Chromosomes 1, 13, and × showed large areas of copy number change in several patients. We also evaluated if genomic changes correlate with changes in expression of corresponding genes. Selecting larger areas of genome, we observed that copy number changes correlate well with the change in expression of genes in these areas. As expected, we also observed a correlation among changes in copy number, heterozygosity, and gene expression at several chromosomal loci. In a number of instances frequently recurrent changes were observed. For example, recurrent copy number changes in areas spanning 1q42.13-1q44 and 1p12-1p12 of chromosome 1 were seen in majority (12 out of 14 and 13 out of 14) patients, whereas copy number changes in the p arm of chromosome × were present in all patients. Similarly the region of chromosome × spanning xq42.13-xq44 showed change in heterozygosity in majority of patients. We also observed that some of the newly acquired changes in late samples correlated with genomic markers of poor clinical outcome. We evaluated prognostic significance of these changes in 192 uniformly treated patients with MM with genomic gains and losses data from SNP array and survival information. Changes in chromosomal regions 1p12 and xp22.1-xp22.33 frequently observed in late samples were significantly (p = 0.017 and 0.037) associated with poor survival in these patients. These data suggest that MM cells acquire changes associated with aggressive phenotype and shorter survival. In conclusion we observe that MM patients acquire genomic changes at a very high rate; and certain chromosomal regions are more vulnerable predicting poor clinical outcome. These data also suggest a need to target mechanisms mediating genomic instability for therapeutic application.