Chromosomal Shattering – Chromothripsis: Understanding the Genetic Diversity of Osteosarcoma

Background: Many neoplasms have associated genetic mutations that aid in the diagnosis, and sometimes guide treatment. Osteosarcoma is a glaring exception. To-date, over 200 genetic mutations have been identified in cases of osteosarcoma. Many have been identified in only a few or even only one case.

Methods: A review of the relevant literature was performed regarding osteosarcoma genetics.

Results: In 2011, Stephens et al. [1] reported during mitosis a single chromosome can explode as a sudden, catastrophic event. The affected chromosome shatters into tens or hundreds of fragments. These fragments then reassemble in a haphazard manner. The result of this chromosomal shattering and reassembly is the creation of a new chromosome filled with genetic abnormalities. This model is termed: chromothripsis. Deletion of the tumor suppression TP53 locus occurs in chromothripsis along with activation of oncogenic centers.

Some chromosomal fragments are not reincorporated into the reconstituted chromosome and form circular DNA fragments. These circular DNA fragments also play an important role in oncogenesis.[2]

Chromothripsis is also present in many other neoplasms. [3] 74% of osteosarcomas have chromosomal evidence of chromothripsis. In 50% of osteosarcomas TP53 inactivation and oncogene amplification occur together. [4]

Conclusions: Chromothripsis is a catastrophic event that creates a sudden chromosomal rearrangement with generation of new mutation, inactivation of tumor suppression loci and activation of oncogenic centers with an increase in detrimental circular DNA fragments.

References:

1. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 44:27–40.

2. Breaking the vicious circle: Extrachromosomal circular DNA as an emerging player in tumour evolution. Seminars in Cell and Developmental Biology. 2022; 123:140–150.

3. Scrambling the genome in cancer: causes and consequences of complex chromosome rearrangements. Nature Reviews Genetics. 2024; 24:196-210.

4. Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution. Cell. 2025; 188:352–370