The bridge to mutagenesis.

Top Line: How might single-cell events jumpstart the extreme complexity and heterogeneity of the cancer genome?

The Study: A few months back, we learned about a huge international collaboration (PCAWG) seeking to sequence the entire genome of thousands of tumors. One of the key events in many tumors was a process called chromothripsis. We usually think of the cancer genome gradually accumulating mutations over successive generations. Unlike that process, chromothripsis is a sudden, catastrophic chromosomal event that results in a cluster of thousands of rearrangements and mutations within a chromosome. This study suggests that such a catastrophic event in a single cell can rapidly produce a complex cancer genome. It all begins with a chromosome bridge that is broken during cell division. This leads to limited chromothripsis at these torn chromosome ends  However, as cells enter further rounds of mitosis, these fragmented bridge-stubs become a hotspot for mutations and structural events that lead to a cascade of further chromothripsis. What happens is a big bang of sorts for the cancer genome. This cascade creates the structural basis for rapid accumulation of DNA damage. In addition, the successive chromosome bridging and associated chromothripsis events can quickly produce the hallmark subclonal heterogeneity of the cancer genome. 

TBL: Catastrophic single-cell events have the capacity to rapidly generate complex cancer genomes and subclonal heterogeneity. | Umbreit, Science 2020