Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients

Abstract

Multiple myeloma (MM) develops from a premalignant plasma cell proliferative disorder, and with time can progress to a more aggressive disease in extramedullary locations. The gradually clinical evolution is supported by clonal expansion of cells that acquire genetic lesions over years. This model of cancer evolution based on ongoing genomic instability mechanism may apply to development of most MM cases. However, in a small fraction of newly diagnosed MM who relapse quickly and finally die within 2 years, the gradual model appears to be untenable. Analysis of high resolution copy number profiles obtained using single nucleotide polymorphism array data from 764 newly diagnosed MM identified large numbers of genomic rearrangements with the hallmarks of chromothripsis in 1.3% of samples. Moreover, this catastrophic event confers a poor outcome. Because chromothripsis appears to occur in a single crisis, our results suggest that high-risk MM patients use this novel way of cancer evolution.

Figure 1

Chromothripsis patterns in newly diagnosed MM patients. Assessment of DNA copy number changes by using genotyping SNP6 microarrays. (Top row) The total copy number (log scale), with the heat map below. (Middle row) The contribution of each allele to the copy number (minimum allele is in black and maximum allele in gray). (Bottom row) Allelic ratio for each SNP (homozygous SNPs cluster at ratios ∼ −1 and 1 and heterozygous SNPs ∼ 0). Genomic location (Mb) is indicated on the bottom. (A) MM_#06358 patient, copy number profile of chromosome 2. (B) MM_#10389 patient, copy number profile of chromosome 1q. (C) MM_#09402 patient, copy number profile of chromosome 3q. (D) MM_#11762 patient, copy number profile of chromosome 16q. (E) MM_#06415 patient, copy number profile of chromosome 16q. (F) MM_#08186 patient, copy number profile of chromosomes 16q and 17. (G) MM_#07545 patient, copy number profile of chromosomes 1q and 3q. (H) MM_#10217 patient, copy number profile of chromosomes 10p and 12q. (I) MM_#10353 patient, copy number profile of chromosomes 8q and 18q.