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Columbia University-led Study Highlights Bionano Optical Genome Mapping Concordance with Cytogenetics

NEW YORK – Optical genome mapping technology from Bionano Genomics shows complete concordance with traditional cytogenetics methods, and can find new genomic markers that could help inform prognosis or therapy, according to new data from a US-based study of patients with acute myeloid leukemia.

"Our primary hypothesis was that we'd get results from a single assay concordant with multiple gold-standard technologies," Brynn Levy, a pathologist at Columbia University Medical Center (CUMC), said in a presentation Thursday at the American College of Medical Genetics and Genomics annual clinical genetics meeting, held virtually this year. In a study of 100 patients with AML, optical genome mapping showed 100 percent concordance, he said.

"The exciting finding is that we identified clinically relevant structural variants or copy number variants in 11 percent of cases that were missed by routine methods," Levy added, including three cases deemed to be normal by cytogenetics methods and reclassified as having translocation events involving cryptic rearrangements.

The data track with recent Europe-based studies using Bionano's Saphyr platform, which suggest optical genome mapping can find nearly all genetic aberrations shown by several different assays.

"It is very intriguing to see this comprehensive and large study," Alexander Hoischen, a researcher at Radboud University Medical Center in the Netherlands who led one of the European studies of Saphyr for cytogenetics, said in an email. "This validates our own findings with very similar results and concordance with standard-of-care. The high degree of analytical validity and promise for clinical utility make a convincing case for use of optical genome mapping in routine soon. This really becomes a very efficient alternative to standard cytogenetic assays."

Bionano's Saphyr provides long-range information on genomes by analyzing molecules of DNA that can reach 3 Mb, with an average of more than 200 Kb. Though optical mapping's genomic resolution is only 500 bases, it outspans long-read sequencing methods, which usually top out on the order of 100 Kb, with average read lengths in the tens of kilobases.

Optical mapping has become important to de novo human genome assembly, such as with the Human Pangenome Reference Consortium's work, but Bionano's biggest plans for Saphyr are squarely in the clinical realm. The firm has previously said it is trying to get Saphyr adopted by approximately 2,500 cytogenetics labs around the world, especially for applications in constitutional genetics and hematologic oncology.

In the CUMC-led study researchers analyzed genomes from peripheral blood or bone marrow samples from patients being treated with chemotherapy. In addition to using optical mapping, researchers analyzed samples with routine karyotype analysis at a CLIA/CAP laboratory; 19 samples also were tested with fluorescence in situ hybridization and three samples underwent chromosomal microarray analysis. 

In addition to concordance, the researchers looked at whether they could identify novel cytogenetic aberrations that could provide further insight into the pathogenicity of AML and other cancers.

The work "certainly does lay the groundwork for multiple future studies, not only in AML, but multiple types of cancers," Levy said.

Optical mapping refined aberrant findings in 13 percent of cases, and in eight out of 52 cytogenetically abnormal cases it revealed clinically significant new events. Three cases were cryptic translocations involving gene fusion partners missed by other methods; two of the cases were NUP89-NSD1 events, which are not yet included in the 2017 European LeukemiaNet guidelines for diagnosis and management of AML patients, but for which there is literature suggesting it is related to adverse outcomes, Levy noted.

It also helped adjust patient risk stratification, according to the 2017 ELN criteria. In one patient, optical mapping results helped upgrade risk scoring to adverse from intermediate and in another patient downgraded it from intermediate to favorable.

"Hopefully, optical genome mapping has the potential to identify novel findings that may be included in future revisions to the risk stratification," Levy said.

Bionano CEO Erik Holmlin called the study "an incredibly important milestone" for the company. "It allows us to illustrate to folks seeking to adopt the system how it's being utilized" in research assay development, he said, which could eventually end up as laboratory-developed tests. It also is helping the company recruit additional researchers in a larger study looking a broader aspects of optical mapping beyond concordance with traditional cytogenetics methods, including its diagnostic yield.

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