Multiple Myeloma (MM) Is Characterized by Genomic Instability Regardless of Ploidy Categories and Degree of Karyotypic Complexity Is an Important Prognostic Factor.

Abstract

MM is characterized by widespread genomic instability. Two broad genetic subtypes of MM defined by ploidy exist. Hyperdiploid MM (H-MM) is characterized by trisomies of chromosome 3, 5, 7, 9, 11, 15, and 19, and generally lacked primary translocations involving the immunoglobulin heavy chain locus (IgH) whereas the non-hyperdiploid MM (NH-MM) is characterized by primary IgH translocations such as t(11;14), t(4;14) and t(14;16). Using high-density array comparative genomic hybridization (aCGH, Agilent 44K array), we catalogued the different aberrations on each chromosome arm and also the total number of aberrations per tumor (NAPT), as an indication of the degree of genomic instability, in a large cohort of 194 MM patients. Both H-MM and NH-MM have high number of genomic aberrations, 15.8±7.5 (mean ± standard deviation) versus 20.6±17.0 respective. NH-MM has significantly more genomic losses (11.8±11.0 versus 4.1±3.8), whereas H-MM has slightly more genomic gains (11.7±5.0 versus 8.8±9.0). Most of the abnormalities in NH-MM are structural abnormalities whereas they are mainly whole chromosome abnormalities in H-MM. Based on these abnormalities, we cluster the patients using hierarchical clustering. The 2 main branch of the resulting dendogram delineate hyperdiploid and non-hyperdiploid patients. Sub-clusters of each ploidy subtype are apparent. For H-MM, a cluster with mainly trisomies, including that of chromosome 21, and another cluster with additional deletions (13, 16q, and less trisomy 21 and trisomy 11) were apparent. For NH-MM, a group with 1q amplification and 13 deletion, which also tend to have loss of chromosome 4, 6q, 16q and 14, and another group with little abnormalities or just 6q loss, and chromosome 13 and 14 loss were identified. We identified some genetic difference between NH-MM and H-MM in additional to known difference such as the trisomies and chromosome 13 deletion. Loss of chromosome 4 (18% versus 0.9%, p<0.0001), loss of chromosome 14 (33% versus 16%, p=0.02) and loss of chromosome 22 (21% versus 4%, p=0.0008) are more common in NH-MM. Based on the distribution of NAPT, a cut-off of 20 abnormalities per tumor segregate the patients into 2 groups with significantly different survival. Those with greater NAPT have significantly shorter survival (median overall survival of 20 months versus 88 months, Log-rank p=0.006). There is no correlation between NAPT and ploidy or presence of chromosome 1 abnormalities suggesting that genomic complexity itself is associated with survival. Our study showed that both H-MM and NH-MM are genomically unstable although the pattern of abnormalities is distinct. In addition, based on clustering analysis, new pattern of genetic abnormalities are observed that allow further refinement of the ploidy subtypes. In addition, genomic complexity is also an important prognostic factor.