The Architecture and Evolution of Cancer Neochromosomes

Abstract

We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is amplified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, amplified oncogenes are overexpressed, while coamplified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.

Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer

“…We validate the feasibility of using the Irys optical mapping system from Bionano Genomics to capture extensive CGRs in a previously reported well-differentiated liposarcoma cell line T778, commonly known as 778, derived from an elderly woman with retroperitoneal relapse (Pedeutour et al 1999). Multicolor fluorescence in situ hybridization showed substantial translocations in this cell line, and short-read sequencing of two flow-isolated neochromosome (derivative chromosome) isoforms further confirmed extensive rearrangements with a predominance of intrachromosomal translocations (Garsed et al 2014). We integrate whole-genome mapping with short-read sequencing to further refine the reconstruction of complex genomic rearrangements.…”

“…There are several lines of evidence suggesting that although genome mapping was performed on the entire 778 cell line, the 72 fusion maps identified largely correspond to the two neochromosome isoforms previously sequenced (Garsed et al 2014). First, CGR and copy number profiles of the fusion maps strongly recapitulate those derived from the two neochromosome isoforms ( Fig.…”

“…It is important to point out that genome mapping was performed without first isolating the neochromosomes as in the original sequencing study (Garsed et al 2014). In summary, a total of 798,063 molecules longer than 150 kb were captured and de novo assembled into 3338 consensus genome maps (Table 1; Supplemental Data S1).…”

“…To evaluate the ability of optical mapping for the detection of CGR, we performed whole-genome mapping on the 778 liposarcoma cell line (Pedeutour et al 1999;Garsed et al 2014). It is important to point out that genome mapping was performed without first isolating the neochromosomes as in the original sequencing study (Garsed et al 2014).…”

GRIDSS: sensitive and specific genomic rearrangement detection using positional de Bruijn graph assembly

“…To evaluate the performance of GRIDSS on complex genomic rearrangements, SVs were predicted in three published cancer-associated neochromosome data sets (accession ERP004006) (Garsed et al 2014; see Supplemental Materials for further details). Each neochromosome contains hundreds of genomic rearrangements identified from the integration of copy number and discordantly aligned read pairs, followed by extensive manual curation.…”