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How do you solve a problem like a broken chromsome?

Cancer. The big “C”. If it hasn’t already I’m sure it will impact your life. Whether or not you are diagnosed, you undoubtedly know someone who has been or will be. From your twenties onwards you are subjected to annual screens for various common cancers. Cancer is a constant and relentless topic of discussion or worry, and it has no cure. Terrifying, right?

While there is no one “cure for cancer”, and there likely never will be due to the wide variety of manifestations of the disease, there are treatments of varying effectiveness. The best treatment we have for cancer at the moment is early detection followed by immediate action. The American Cancer Society recommends a whole gamut of tests that you and I should have throughout our life. If you’re a woman, you need to be regularly checking for breast and cervical cancer; if you’re a man it’s your prostate you should be worried about. The reason this early detection method works is that cancer is generally regarded as a progressive condition that takes time to develop, both at the genetic and clinical level.

Over a lifetime the human body is subjected to a variety of potentially carcinogenic (cancer-causing) insults. Ultraviolet rays, ionizing radiation, and pollution to name a few. The reason these things have the ability to damage a cell and point it along the path to malignancy is that they can damage our DNA. They can modify or break DNA such that the information encoded becomes corrupted. So why aren’t we all seriously ill by the age of 30? We have proteins within our cells that can actually recognize and repair certain lesions present on our chromosomes. These proteins comprise the “DNA repair machinery”, and like any toolkit, it contains heavy-duty equipment for dealing with large holes, and more precision gear for small chips and scuffs. But sometimes this machinery makes a mistake, or misses a damaged gene, or is simply overwhelmed with the amount of damage done, and this is when a cancer causing mutation can emerge.

There are a variety of different mutations and a plethora of different genes that can cause cancer, but the end result in all cases is that the cell gains a function that allows it to thrive. Generally, early mutations result in a faster rate of growth and division, allowing the cancerous gene to propagate. These faster growing cells are more likely to accrue yet more mutations, and thus the cancer gradually progresses. However, as shown in a paper published this month in Cell (which is incidentally the most aesthetically pleasing scientific journal out there), this is not the only way a cancer can be born.

If the conventional, gradual progression view of cancer is like a Rubik’s Cube, with bits of DNA gradually being changed or moved around, then this new discovery is a jigsaw puzzle. The study, conducted primarily at the Wellcome Trust Sanger Institute in Cambridge, UK, details a number of clinical cases of cancer in which the initiating event was a dramatic fragmentation of a chromosome. Normally when such a catastrophic event occurs, the cell would be expected to sacrifice itself in a process called apoptosis, or programmed cell death. But in these cases, the DNA repair machinery appears to have glued everything back together. In an effort to solve the genetic jigsaw puzzle quickly however, pieces were lost or forced into the wrong places, resulting in mutations. The fact that the cell lived indicates that the repaired chromosome, while not looking exactly like its former self, could now perform a novel cellular function, thus giving the cell an advantage over its neighbor and priming the cell to become cancerous.

Reports circulating in the press are calling this phenomenon the “Humpty Dumpty” effect. In the rhyme “all the King’s horses and all the King’s men couldn’t put Humpty together again”. But the DNA repair machinery could, albeit with a few critical mistakes. In the paper, the authors propose the far more formal term “chromothripsis” from the Greek “chromos” for chromosome, and “thripsis”, which means shattering into pieces.

The research presented in this paper is painstakingly detailed and state of the art. In order to initially identify the drastically altered chromosomes new sequencing technology was extensively used. So-called deep sequencing has been around for only a few years, and is still of limited availability to scientists with restricted financial resources. In addition, complex computer modeling was required to analyze the sequence data and to verify the chromothripsis hypothesis.

Interestingly, while Humpty Dumpty chromosomes are present in a wide variety of cancers, there is a much higher incidence in bone cancers. In 25% of the bone cancers analyzed (osteocarcinomas and chordomas) chromothripsis was identified, whereas in the overall sample it was only seen in 2-3% of cases. It is currently not clear why this could be, but this observation could increase our understanding of this cancer-causing event.

As a molecular biologist I am naturally curious as to how this process happens. How does the cell manage to put the chromosomes back together and save its own life? The organization of the reassembly, i.e. that the chromosome pieces are put back together within the correct chromosome rather than being spread across all 46, suggests that the event has to occur during a certain phase of the cell’s life cycle, right before the cell divides. During this phase the chromosomes are tightly packaged and take on these characteristic shapes:

But of course you and I are still left wondering what causes this disastrous cellular event. What crazy carcinogen should we be avoiding? The authors propose that ionizing radiation could be to blame, as it is known to cause breaks in DNA. The best part about this theory is that it can easily be tested in a laboratory situation, and I hope to see such a study published in the next few years. Intriguingly, the authors also suggest that this could potentially be a naturally occurring event gone wrong. They cite the case of Influenza virus, which naturally re-assorts its genome to evade host immune responses and gain evolutionary fitness. Similarly bdelloid rotifers, microscopic marine animals, can repair extensive DNA damage after dehydration, and do so with sufficient accuracy that they can survive.

So if cancer can begin in one massive genetic explosion, is prevention still the best way to tackle the disease? While this new discovery is striking, we shouldn’t forget that it was only observed in 2-3% of the 746 clinical samples tested. The bigger concern is why this event is more likely to occur in bone cancers, which are typically very difficult to treat. So don’t stop your preventative visits to your doctor; early detection is still key in the fight against cancer.

Katie Ph.D. ABD

Comments

CM Doran
Reply

Wow…how cool is that research? Have you read Microcosmos by Lynn Margulis? Maybe this chromothripsis functions for our evolution, derived from our symbiosis with microorganisms? Keep writing Katie!

Katie, Ph.D. (ABD)
Reply

Wicked cool! I haven’t read that book, but I did hear her give a talk to the Brown geology department and it was fantastic. It is interesting to think about this as a driver of evolution. In fact as I was researching the article, I was reading about two opposing theories of evolution. The first is “Gradualism”, which hypothesizes that species gradually evolve over time through the steady accumulation of advantageous mutations. The other theory, “Punctuated Equilibrium”, postulates that rare but dramatic changes in an organism’s genome cause a sudden speciation event. Chromothripsis-like events could be important in the latter model. I should look out that book at the library…

katiephd
Reply

Hi R, Thanks for reading! I took a look at your take on the paper. I’m afraid I haven’t read the Hicks paper, but I will try and do so soon. However regarding this paper I agree, they do not directly show that chromothripsis occurs in one catastrophic event. That being said, they do substantial modelling of the various genetic events that could hypothetically cause these rearrangements and these data are, in my mind, very convincing. They conclude that if these aberrations were occurring throughout multiple generations they would not be restricted to single chromosomes. I am perhaps not doing this justice, but their analysis is presented in Figure 5. As I mentioned, I would love to see a follow up study to analyze what types of insults could induce such a catastrophe, as well as a more detailed understanding of the cellular machinery that sticks the “humpty dumpty chromosome” back together again.

RK

K,

Check out my cancer book reviews:
http://www.cancer-modeling.org/main/?cat=3

read the books, if the big C interests you.
I know, I am off-topic, fig. 5 bothers me, their model and simulations are Weird.
Reread how fig.5 is done. I can just as well make a “gradual” model that will generate
thripsis patterns.

R

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