Shattered chromosomes cause cancer chaos

At its heart, cancer is caused when our genes – the instructions encoded in the DNA found within our cells – go wrong. Without the correct instructions, cells start to multiply out of control, fail to die when damaged, and begin to spread around the body.

Scientists studying the precise nature of these microscopic – yet potentially disastrous – errors have found all kinds of weird and wonderful mistakes. These range from very specific ‘typos’ to large scale rearrangements.

To use an analogy, if the entire DNA of a cell (its genome) is a bit like a recipe book, then some genetic faults are the equivalent of simply changing ‘tomato’ into ‘potato’, while others are akin to ripping whole pages out and shuffling them around.

But recent revolutionary research from scientists in the US and UK has revealed a completely different – and catastrophic – way for DNA to get messed up.

Shattering the peace

Published in the prestigious journal Cell, this groundbreaking work comes from the Cancer Genome Project team, who brought us the first fully mapped cancer genomes at the end of 2009. Since then they’ve been busy analysing DNA from samples taken from many different types of cancer and trying to spot interesting patterns in the data.

Since the 1970s, the prevailing view has been that cancers ‘evolve’ gradually, picking up a few new faults each time a cell divides.  This idea is supported by plenty of research into cancer genomes over the years.

But in their latest investigations, the Cancer Genome team noticed a few examples that bucked this trend. Instead of the hallmarks of gradual change – a few ‘typos’ here, a couple of ‘page shuffles’ there – the researchers discovered evidence of something much more sudden and catastrophic.

Within our cells, our DNA is arranged into individual pieces known as chromosomes, and 46 chromosomes are found in virtually all human cells.  If the entire DNA of a cell is analogous to an instruction manual, then chromosomes would be individual ‘chapters’.

In a few cancer samples, the scientists found that one or two whole chromosomes had been literally shattered to pieces and stitched back together in a haphazard way – not so much shuffling the pages of the genetic recipe book as completely ripping them to pieces and randomly gluing the bits back together. The researchers call this “chromothripsis” – thripsis being Greek for “shattered into pieces”.

This didn’t seem to be a vanishingly rare event either. Two to three per cent of cancers studied by the team so far show the signs of chromothripsis (across a wide range of different cancer types). And in some cancer types it seemed to be even more common – for example, around a quarter of bone cancer samples had shattered chromosomes.

Unanswered questions

While the research is impressive and significant, it raises a number of questions.

For a start, we don’t yet know what impact chromosome shattering has on cancer cells. It may look messy, but does this cut-and-paste genetic chaos actually have a major role in driving the growth and spread of cancer? The chances are that it does, but this needs to be understood in detail.

Next – how does it happen? Back in the 70s, researchers showed that under certain conditions in a dividing cell, chromosomes could find themselves in the wrong place at the wrong time, causing them to shatter. Is this same process at work in cancer cells?

Another mystery is why the team only ever found one or two shattered chromosomes in a cell. It seems strange that such a catastrophic event would be restricted so neatly, so what’s going on? There is evidence that individual chromosomes can get stuck in little ‘pockets’ caused by unruly cells division in tumours, but at the moment it’s not clear what’s going on in the case of chromothripsis.

Finally, how are the pieces of DNA stuck back together? Is there any discernible pattern, or is it random? Which technique does the cell use to ‘glue’ the ends together, and can we exploit this to try and treat cancer more effectively – for example by switching the repair process off, leaving cancer cells so damaged they can’t survive?

Getting answers to these questions may not be simple, and will require a lot more research.

Where now?

The discovery of chromothripsis is completely new, and reveals a previously unknown mechanism for messing up DNA in cancer cells.  Instead of gradually getting more and more chaotic, the researchers think that chromosome shattering could suddenly lead to a major change in a tumour – for example, switching a slow-growing cancer into a fast-growing one in a single, disastrous step.

Furthermore, the fact that chromothripsis seem to happen across a wide range of cancer types suggests that it’s likely to be a general property of cancers in general. And it looks like the process might be even more important in a significant proportion of bone tumours.

As the Cancer Genome Project speeds ahead, along with linked efforts around the world, there is a wealth of information being generated about the genetic changes that underpin cancer.

This discovery – along with the many others that will doubtless follow in it footsteps – is an important step along our journey to truly understanding the disease on a fundamental level. This knowledge is the key to ultimately beating cancer.

Kat

Reference
Stephens PJ, et al (2011). Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell, 144 (1), 27-40 PMID: 21215367