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Bionano Customers Explore Diagnostic Applications of Genome Maps in Cancer, Genetic Disorders

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NEW YORK (GenomeWeb) – Several Bionano Genomics customers have recently been testing the firm's Saphyr optical genome mapping platform for clinical applications in hematologic cancer and inherited disease, comparing it against standard cytogenetic diagnostic assays. In the meantime, the San Diego-based company has been working on updates that will become available later this year to increase the system's throughput and streamline its sample prep workflow.

Researchers at several institutions in the US have begun testing Bionano's system against karyotyping, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization (array CGH) to see if it could be used for the diagnosis of hematologic cancers. In addition, in a study published last month, researchers in China compared Bionano's technology to standard methods Southern blotting and FISH for diagnosing an adult form of muscular dystrophy.

According to Bionano CEO Erik Holmlin, multi-institutional studies seeking to demonstrate the utility of the Bionano technology for blood cancer diagnostics are underway in Europe and the US, and preliminary results are expected by the middle of this year. "We see the Bionano Saphyr in the future playing a role in hematology-oncology testing, solid tumor testing, and constitutional disorders as a way of modernizing the workflows that involve FISH, karyotyping, and microarrays, and in many settings, consolidating those three workflows into one," he said.

Bionano's single-molecule optical genome mapping technology works by isolating very high molecular weight DNA, cutting and fluorescently labeling the DNA at specific sites, flowing single labeled DNA molecules into nanochannels on a chip to stretch them out, imaging the labels on the Saphyr instrument, and assembling patterns from several molecules into a genome map. Comparing this map against a reference allows the company to detect structural variants ranging in size from about 500 bases to several megabases.

Bionano has been venturing into clinical applications for some time. In 2016, it teamed up with Berry Genomics in China to develop clinical assays for a number of conditions related to reproductive health and to obtain approval for Bionano's system from the China Food and Drug Administration. Also, in 2017, the company partnered with hematopathology company Genoptix to develop diagnostic assays for hematologic cancers.

Holmlin said that both collaborations are still ongoing. In China, he said, new regulatory paths to commercialize clinical tests have opened that do not necessarily require the approval of an instrument, but Bionano is still working with Berry Genomics to develop assays for specific clinical indications.

Genoptix, he said, is seeking a more streamlined workflow for the Bionano platform, in particular, the sample preparation part, which currently takes several days and involves an agarose matrix to extract long DNA fragments. Bionano has been working on faster, solution-based DNA extraction methods that are automation friendly and will be commercially available later this quarter. "That is going to be a big driver at places like Genoptix and other hematology-oncology labs," Holmlin said.

In addition, the company is working on improving the throughput of the system. Last year, it upped the number of samples that can be run on one chip from one to two, and "we expect that to continue to increase," he said. The instrument speed will also go up, so two chips can be run per day. "Those innovations will be rolling out this year and will make the system faster and cheaper," he said.

Consumables costs for a genome-wide structural variation analysis currently total $500 per genome, he said, "but we expect that cost will continue to go down." He declined to provide a list price for the Saphyr instrument but said that it is comparable to a high-end microarray scanner or an Illumina NextSeq sequencer.

Last year, Bionano also partnered with clinical genome informatics firm Genoox to integrate its data with Illumina sequencing data, which Holmlin said will be very important for clinical and research applications. "There is really a perfect overlap in genome variation sensitivity between the Bionano system and Illumina's short-read sequencing," he said. "Those two data types provide researchers and clinicians with the ability to comprehensively detect all variants in a sample."

There is no fundamental reason why data from Pacific Biosciences — the long-read sequencing firm Illumina is in the process of acquiring — could not be integrated, as well, but at the moment, he said, PacBio's turnaround time is too long and its data too costly to fit into a clinical workflow.

In the meantime, a multi-site study is comparing the Bionano technology to the gold standard diagnostic technologies of karyotyping and FISH for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). These types of cancer often come with copy number changes or genomic rearrangements that have diagnostic or prognostic value and can be used to tailor a patient's therapy, but currently available technologies are all limited by their resolution.

The study, which recently started and involves researchers at Columbia University, MD Anderson Cancer Center, the Mayo Clinic, and Augusta University, aims to analyze 100 to 200 AML or ALL patient samples and is expected to be completed at the end of this year or early next year.

Brynn Levy, a professor of pathology and cell biology and director of the clinical cytogenetics laboratory at Columbia University Medical Center, who is coordinating the study, said the initial goal is to validate the Bionano platform and see whether it can consistently pick up the same genomic changes that can be observed by karyotyping and FISH. In addition, the study will compare Bionano to mate-pair sequencing, which the Mayo Clinic's laboratory has been using to detect structural rearrangements in hematological cancers and congenital diseases.

The idea is to analyze the same bone marrow samples used for standard testing and compare the results side by side, said Levy, whose lab will extract the DNA and run it on the Saphyr platform. He said one advantage of the Bionano technology is that it could potentially replace several individual tests with a single assay. "Right now, we do karyotyping and multiple rounds of FISH, " he said, and Bionano's ability to pick up copy number changes and structural rearrangements, particularly balanced ones, "makes it very attractive because we have many balanced rearrangements as some of the hallmark changes we see in these cancers."

A second goal is to test whether the Bionano platform can pick up additional alterations that karyotyping or microarrays miss, such as subtle or balanced rearrangements, inversions, or insertions, Levy added.

Whole-genome sequencing, he said, would also be able to pick up such alterations but is currently too expensive and complex. "Ultimately, we may go to whole-genome sequencing for everything, but there is still way too much that needs to be done in preparation for this being a mainstream test, and that has to do with bioinformatics and experience," he said.

Levy said the biggest challenge adopting the Bionano technology for clinical testing is its current low throughput, which would not be sufficient for a lab that needs to process more than a few samples per week. In terms of cost, he said, Bionano might end up being more cost effective if it replaces several other technologies, though he has not done a cost analysis.

In addition to Bionano's technology, his lab is looking at exon microarrays, which he said might complement exome sequencing. "You would see a mutation on one allele and potentially a deletion or duplication on the other allele in the same gene that you would miss by doing a single technology," he said.

Rashmi Kanagal-Shamanna, an assistant professor and director of the microarray laboratory at the department of pathology's molecular diagnostics lab at MD Anderson Cancer Center, is involved in the same multi-center study. In addition, she is conducting a study in collaboration with Bionano that is comparing the firm's platform with karyotyping, FISH, and array CGH in about 20 patients with AML or myelodysplastic syndrome (MDS).

Similar to the multi-center study, the goal is to see whether Bionano can identify all alterations that are picked up by the standard techniques and whether it can find any novel genomic alterations that might be clinically significant. Kanagal-Shamanna said that array-based techniques, for example, miss subclonal alterations that occur in fewer than 30 percent of the tumor cells, which she hopes Bionano would be able to identify. The goal is to present results from the study, which is currently ongoing, at a scientific meeting later this year.

She said one challenge for implementing the technology clinically is its current high cost, and another is the need to obtain and store fresh tissue samples, which is more expensive than storing DNA or slides. "But I think with time, if there is enough invested in this technique, I don’t see any problem to overcome these two barriers," she added.

Like Levy, she also cited the limited throughput of the Bionano platform as a potential obstacle for clinical implementation, especially at places like MD Anderson, where bone marrow samples from 60 patients need to be analyzed every day.

In addition to testing Bionano, her lab is looking into extracting copy number change information from short-read sequencing data that the lab already generates routinely for mutation analysis.

Other groups have been focusing on the diagnosis of constitutional disorders as a potential clinical application of the Bionano platform. In their recent publication in Molecular Genetics and Genomic Medicine, for example, researchers at Whenzhou Medical University and Berry Genomics in China used the Bionano technology to analyze samples from patients with facioscapulohumeral muscular dystrophy 1 (FSHD1), an autosomal dominant adult muscular dystrophy that is caused by the shortening of a repeat array near the telomere of chromosome 4. The disease is currently diagnosed by Southern blot or FISH, which the researchers said is difficult and time consuming.

In their paper, they showed that Bionano's optical mapping correctly diagnosed the disease in a five-generation family afflicted by FSHD1. The assay they developed is "relatively simple and achievable by most operational molecular laboratories, and so this form of genome mapping broadens the options for FSHD1 disease diagnosis," they wrote, adding that it might also be suitable for prenatal applications. They cautioned, however, that "it is still early days in the application of this new technology and costs may be currently prohibitive for general routine applications."

In addition to confirming patient results, the Bionano platform discovered a new structural variation within the repeat in patients who appeared to have a milder form of the disease, though further studies need to confirm a causal relationship.

Holmlin said one advantage of the Bionano system in that study was that it could tell apart repeats occurring on chromosome 4 and on chromosome 10, which are very similar, whereas Southern blotting has trouble distinguishing what chromosome the repeats originate from.

He added that the company expects Berry Genomics and its collaborators to explore additional clinical applications for the Bionano system that currently require cytogenetic testing, both for constitutional disorders and for cancer.

Columbia's Levy said he is also testing the Bionano platform for genetic disorders, applying it to patients with balanced genomic rearrangements to identify genes that got disrupted by the rearrangement. That project, he said, will also be looking at whether optical mapping can detect subtle changes that were missed by current technologies.