The Architecture and Evolution of Cancer Neochromosomes

We isolated and analyzed at single nucleotide resolution cancer-associated neochromosomes from well-/de-differentiated liposarcomas. Neochromosomes, which can exceed 600Mb 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 over-expressed, while co-amplified 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 provides insight into the dynamic mutational processes underlying the life history of a special form of cancer mutation.