Abstract
Extramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). EMM is frequently associated with high-risk cytogenetics, but their complex genomic architecture is largely unexplored. We used whole-genome optical mapping (Saphyr, Bionano Genomics) to analyse the genomic architecture of CD138+ cells isolated from bone-marrow aspirates from an unselected cohort of newly diagnosed patients with EMM (n = 4) and intramedullary MM (n = 7). Large intrachromosomal rearrangements (> 5 Mbp) within chromosome 1 were detected in all EMM samples. These rearrangements, predominantly deletions with/without inversions, encompassed hundreds of genes and led to changes in the gene copy number on large regions of chromosome 1. Compared with intramedullary MM, EMM was characterised by more deletions (size range of 500 bp–50 kbp) and fewer interchromosomal translocations, and two EMM samples had copy number loss in the 17p13 region. Widespread genomic heterogeneity and novel aberrations in the high-risk IGH/IGK/IGL, 8q24 and 13q14 regions were detected in individual patients but were not specific to EMM/MM. Our pilot study revealed an association of chromosome 1 abnormalities in bone marrow myeloma cells with extramedullary progression. Optical mapping showed the potential for refining the complex genomic architecture in MM and its phenotypes.
Highlights
Extramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM)
The infiltration of myeloma cells in bone marrow (BM) aspirates based on immunophenotyping was highly variable in enrolled patients (3–36%); more than 10% infiltration of plasma cells was found in the BM smears of all enrolled patients
Optical mapping was performed in all enriched samples with the following run parameters: average effective coverage, 154×; collected data per sample, 699 GB (427– 1710 GB); DNA molecule size (N50), 316 kbp (219–446 kbp); label density 17.3 labels per 100 kbp (14.1–22.6); and map rate, 74.4% (41.5–93.3%)
Summary
Extramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). Patients present with extramedullary disease (EMM), in which myeloma cells spread to other organ s ystems[1,2,3] This aggressive and mostly treatment-resistant sub-entity of MM can either accompany a newly diagnosed disease, occurring at a frequency of 3–18%4,5, or develop with disease progression or relapse, with a frequency of 6–20%4,6. We applied novel whole-genome optical mapping to investigate the complex genomic architecture of BM myeloma cells in newly diagnosed MM and EMM patients. This method has an advantage in detecting small and large structural rearrangements as well as complex rearrangements across the whole genome that are undetectable by traditional methods, such as sequencing and c ytogenetics[14]. A comparison of MM and EMM may help to elucidate genetic events, allowing the dissemination of myeloma cells from BM to blood and distant tissues
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