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Optical Mapping Approach Uncovers Widespread Structural Variation in Multiple Myeloma

NEW YORK (GenomeWeb) – By combining optical mapping with DNA sequencing, researchers from the University of Wisconsin-Madison and elsewhere were able to uncover extensive genomic variation within a multiple myeloma patient.

UW-Madison's David Schwartz and his colleagues analyzed a patient's tumor at two time points alongside normal tissue from that patient to uncover structural variants, as they reported in a paper to appear online at the Proceedings of the National Academy of Sciences this week.

"It's a rare, near-complete characterization of the complexity of a myeloma genome, from the smallest variance all the way to big chunks of chromosomal material that differ between the tumor DNA and the normal DNA of the patient," co-author Fotis Asimakopoulos, a clinician at the UW-Madison School of Medicine and Public Health, said in a statement.

It also, the researchers argued, showed the potential of an optical mapping-based approach.

"The approach allows an intimate view of a cancer genome," Schwartz added. "You get to see it, you get to measure it, and you get to see it evolve at many levels. This is what we should be doing with every cancer genome and the goal here is to make the system fast enough so this becomes a routine tool."

The researchers collected non-tumor and tumor samples from one patient — from while the disease was still responding to treatment and again after it'd become resistant — and performed both optical mapping and DNA sequencing on all samples. Optical mapping, they noted, is a single-molecule system that generates large datasets of ordered restriction maps from single DNA molecules that they routed through a cluster computing-powered analysis pipeline to uncover structural variants and large-scale copy number changes in a relatively unbiased manner.

By comparing the resistant multiple myeloma samples with the normal sample, the researchers uncovered widespread genomic gains and losses. The resistant multiple myeloma sample harbored additional large-scale rearrangements not found in the earlier treatment-sensitive multiple myeloma sample, indicating to the researchers that there's an increase in copy number changes with tumor progression.

These findings, they added, largely squared with DNA sequencing-based CNV analysis.

As their consensus optical maps provided "nearly telomere to telomere information" about the tumor genomes, the researchers then investigated at a finer scale. They combined their analysis of chimeric consensus maps — formed through intrachromosomal or interchromosomal rearrangements — with DNA sequencing-based structural variation analysis to characterize 31 of the 37 copy-number breakpoints they uncovered in the drug-resistant multiple myeloma genome and used that to pull together a karyotype of the chromosomes.

They found, for instance, two regions of copy-number loss on chromosome 2 and on chromosome 5; an unbalanced translocation between chromosome 2 and chromosome 10; and a tandem duplication on chromosome 5, among others.

At a zoomed-in scale, the researchers uncovered both canonical and non-canonical genomic gains and losses. For example, they noted a deletion on chromosome 1p that spanned the FAF1 and CDKN2C genes — CDKN2C, they noted, is known to be disrupted early on in multiple myeloma development — and an about 12 megabase deletion on chromosome 17p that encompassed the TP53 gene.

These deletions varied between the drug-resistant and drug-sensitive multiple myeloma samples. Schwartz and his colleagues reported that while the samples shared a number of deletions, the drug-resistant multiple myeloma sample had more than two dozen additional deletions. Of those, seven overlapped with exons.

The tumor samples, the researchers added, also harbored SNPs that had been linked to multiple myeloma, including one in CCND1.

The late-stage tumor sample similarly had an increased number of SNVs — they shared 60 non-synonymous SNVs, but the drug-resistant tumor sample acquired an additional 41 SNVs, again indicating increasing mutational burden with disease progression.

Genes mutated in both tumors could present treatment targets, the researchers noted, as they could represent key mechanisms for multiple myeloma development.

"To cure myeloma, we need to understand how genomes evolve with progression and treatment," Asimakopoulos added. "The more we can understand the drivers in cancer in significant depth, and in each individual, the better we can tailor treatment to each patient's disease biology."

The researchers added that they are now working on ways to increase the resolution of their optical mapping approach as well as making it faster and more cost-effective.