Different cancers reveal distinct mutation patterns, from mismatch repair defects in colorectal cancers through to translocations that generate fusion genes in subtypes of leukemia. Neochromosomes are a form of mutation comprising the somatic acquisition of massive, episomal, self-replicating structures within cancer cells, specific to certain cancer types, including several sarcomas. They are found in about 3% of cancers, but are almost universal in some types of sarcoma.
We isolated and sequenced cancer-associated neochromosomes from 6 well-/de-differentiated liposarcomas and patient tumours. Our analysis has revealed the complex and dynamic life history of neochromosomes. Neochromosomes, which can reach 600Mb in size, are stitched together from multiple chromosomes. Their origins stem from the chromothriptic shattering of chromosome 12q, which is repaired to form a ring chromosome. Neochromosomal material is amplified by the breakage-fusion-bridge mechanism, with DNA from additional chromosomes accumulated through subsequent shattering events, before capture of telomeres ends this amplification process.
Our study provides insight into the oncogenic properties of neochromosomes, including a novel therapy target in sarcoma, and may have broader significance in understanding therapy resistance mechanisms.