A Novel Bead-Capture Nanopore Sequencing Method for Large Structural Rearrangement Detection in Cancer

Rapid, cost-effective genomic stratification of structural rearrangements in cancer is often of vital importance when determining treatment, yet existing diagnostic cytogenetic and molecular testing fails to deliver the required speed when deployed at scale. Next-generation sequencing-based methods are widely used, but these can lack sensitivity and require batching of samples to be cost-effective, with long turnaround times. Here we present a novel method for rearrangement detection from genomic DNA based on third generation long-read sequencing that overcomes these time and cost issues. We demonstrate the utility of our approach for the genomic stratification of patients with Acute Myeloid Leukaemia (AML) based on detection of four of the most prevalent structural rearrangements. Using our method, we not only determine the precise genomic breakpoint for each expected rearrangement, but we discover and validate novel translocations in half of our samples, 75% of which involve known oncogenes. We anticipate this method will prove to be a powerful tool for the diagnosis, genomic stratification and characterisation of cancers.