Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities

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.

Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL)

“…On the other hand, high variability was observed in the number of self-molecules supporting the translocations called by OGM (median: 45; range: 5–175). A total of 27 of the apparently well-covered translocations were based on less than 10 molecules, which is the cut-off used by some authors in hematological studies [ 39 , 40 ]. Thereby, we next evaluated if these low values could also be associated with a higher rate of false-positive calls, but no conclusive results were obtained.…”

“…In contrast, while we were not able to validate two translocations with less than 10 molecules, 22% of the previously known or validated translocations were supported by only five to nine mapped molecules by OGM. Thus, contrarily to some authors that set a minimum of 10 supporting molecules for the analyses [ 39 , 40 ], we recommend not filtering these variants but performing validations with alternative techniques before reporting them. It is remarkable that, since we processed the samples, a new upgrade of Bionano Access has been developed that has improved the filtering of these types of false-positive calls.…”

Optical genome mapping reveals additional prognostic information compared to conventional cytogenetics in AML/MDS patients

“…On the other hand, novel aberrations can probably be detected easily by this method, thus offering a screening tool for development of structural resistance mechanisms and tumor evolution. In the future, the detection rate of aberrations in hematological diseases such as lymphomas or myeloid malignancies with less bone marrow infiltration can certainly be increased by selection or enrichment of cancer cells, as recently has been done in an OGM approach to extramedullary multiple myeloma 54 . Although not reaching the resolution of FISH, OGM is by far more sensitive and especially specific for structural variants not involving the centromere or neighboring regions.…”

Optical Genome Mapping in Routine Human Genetic Diagnostics—Its Advantages and Limitations

“…This limits the scope of OGM when applied prenatally, as triploidies are of diagnostic relevance and can be found in 2–3% of pregnancies and in approximately 8% of miscarriages [ 28 , 29 , 30 ]. Additionally, as for aCGH, we expect difficulties in detecting low-level mosaicism of variants that are solely detected by the CNV pipeline, as seen in earlier data published by [ 31 ]. This would include, besides aneuploidies, unbalanced SVs that were missed by the SV pipeline, such as the duplications of cases S07 and S11.…”

“…This would include, besides aneuploidies, unbalanced SVs that were missed by the SV pipeline, such as the duplications of cases S07 and S11. In contrast, SVs that are detected by a change in the OGM pattern have been shown to be detectable in low-level mosaics at frequencies of >5% [ 31 , 32 ]. The detection of mosaic chromosomal aneuploidies is especially important when analyzing chorionic villi, as placental mosaicism may occur in approximately 1–2% of samples [ 33 , 34 ].…”