Facile Genome-Wide Detection Of Genomic Fusions And Other Somatic Chromosomal Abnormalities Through Bionano Whole Genome Imaging

Genome instability is a key hallmark of cancer. Instability is important because it allows the genome to acquire growth advantage by amplifying or creating oncogenes by fusing otherwise non-pathogenic genes and by deleting/inactivating tumor suppressor genes. Several gene fusions have been discovered and some have been exploited for therapies as they produce fusion proteins that can be targeted by chemotherapeutics such as tyrosine-kinase inhibitors targeting BCR-ABL used to treat CML. In addition, other genomic fusions serve as diagnostic or prognostic indicators important for cancer management. Clinically, fusions are generally detected through targeted assays like NGS panels, PCR and FISH, or through karyotyping. High resolution, whole genome approaches to detect fusions are needed as current approaches have innate limitations, such as karyotyping (low resolution) and whole genome sequencing (blind in the ~66% of the genome containing repeats). Bionano whole genome imaging is able fill in the gaps, providing high resolution (~2kbp breakpoint precision) and ability to span complicated genomic repeats. Here we demonstrate an easy, fluid, largely automated workflow for whole genome detection of fusions and other somatic variants. The Bionano workflow involves a novel rapid isolation protocol for extremely high molecular weight DNA, labeling the DNA to create a barcode across the genome and automated data collection using the Bionano Saphyr system. The assay is inexpensive and the whole workflow can be accomplished from cells/tissue to variant calls within 4 days turnaround time. Because this approach is whole genome and not masked/hidden by repeat elements, we are able to detect novel fusions that have not previously been detected. In a standard assay, whole genome imaging can detect variants at 5% allele fraction and with increased coverage fusions down to 1% allele fraction can be efficiently detected. Whole genome imaging for novel fusion detection and genome instability studies will likely play an increasing role as a complementary genomics tool in cancer research going forward. Citation Format: Alex Hastie, Andy W. Pang, Joyce Lee, Ernest T. Lam, Thomas Anantharaman, Henry Sadowski, Mark Oldakowski. Facile genome-wide detection of genomic fusions and other somatic chromosomal abnormalities through Bionano Whole Genome Imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3543.