Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response.
These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative
chromosomes. Although methods exist for detecting individual fusions, they are generally unable to reconstruct complex
chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome
maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping
(Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome
maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating
the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147
chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference
genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and
place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping
and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a
higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular
relevance to human cancer.