Cutting and pasting our genome
By Jessica De Loma Olson
Can you imagine your cells doing patchwork with your genome? Cutting and pasting together fragments to produce a new work of art. In 2011, a study led by P.J. Campbell from Cambridge defined it as chromothripsis: a single catastrophic event for a chromosome. During a short period of time and in a specific region, the chromosome is cut into fragments and randomly rearranged back together, altering the chromosomic structure. Pure chaos for your initially neatly organized chromosomes.
This process was first described when sequencing the genome of a patient with chronic lymphocytic leukemia. There were 42 rearrangements in chromosome 4. After this initial discovery, the new phenomenon has been linked to 2-3% of all cancer types and 25% of bone cancers. Common cancers with up to 100 rearrangements are melanoma, small cell lung cancer and colorectal cancer, just to name a few.
The importance lies not only in linking this concept to cancer but, if so, how it would change our definition of it. The current idea is a gradual gain of mutations spread through multiple chromosomal locations accumulating over decades. But chromothripsis could shift this paradigm. With only one hit, the structure and the number of copies of multiple genes could be altered. When this happens, typically in biology there are two options: adapt or die. And this is also the case when chromothripsis occurs. If essential genes are affected, the cell will die. But, on rare occasions, the shattering alters genes involved in cell growth and increases it.
If the Hulk existed and needed a biological explanation, chromothripsis would probably be it.
So, what unchains this chromosomic explosion? M. Jones and P. Jallepalli proposed in their 2012 paper in Developmental Cell that DNA double strand breaks (DSB) could be the trigger. Cutting both DNA strands, as if you had a pair of scissors, can be caused in nature by ionizing radiation, failed cell death and stress during DNA replication, among others. Once these DSBs are formed, the cell can fix them in a tidy way by specific repair mechanisms, die if they are unbearable or if this death is avoided, chromothripsis can come into play.
Despite the facts and figures, some scientists are still skeptical. C. Righolt and S. Mai state that for now there is not enough data to confirm that these multiple arrangements actually occur all at once. If it does occur in a single event, is one event enough to lead to cancer? It is also questionable if the concept of chromothripsis fits the idea of tumor heterogeneity, where different cells within the same tumor present distinctive characteristics. All in all, these authors suggest using the safer term complex rearrangements instead of chromothripsis, which implies a specific time frame.
However, no matter if the term is adequate or not, there seems to be some magic behind the science. Fun fact: If the Hulk existed and needed a biological explanation, chromothripsis would probably be it. Scientist Sebastian Alvarado from Stanford University believes that if it were to happen, this chromosomal shattering would be the only current way to explain his superpowers.
But miracles do happen in real life. It is the story of a 58 year-old woman that used to suffer from WHIM syndrome, a genetic immunodeficiency characterized by a mutation in the chemokine receptor CXCR4. She presented warts and multiple infections since birth. At the age of 38, she suddenly stopped having them. She was cured. A study from 2015 published in Cell by D. McDermott and J.L. Gao showed that the affected gene and 163 other normal genes were lost. It was the result of chromothripsis. Gene CXCR4 was just in the right place at the right time, confirming there are always two sides of the same coin. You just have to be lucky when you flip yours.