Biology | Chromosomes and Cancer

What makes a cell become cancerous?

This can happen if the chromosomes are incorrectly distributed to a new cell. The cell could get too many copies of a cancer-promoting gene, or too few copies of a cancer-protecting gene.

The breakage-fusion-bridge cycle is one way that this can happen. This week I was asked to provide a cartoon showing the breakage-fusion-bridge cycle and how it relates to a chromosome abnormality I was describing.

By lucky coincidence my colleague Lan Ta just this week published a paper with a neat breakage-fusion-bridge cartoon that was put together by Bruce Mercer. As well as being a scientist, Bruce is a graphic artist – a very handy combination. So I was trying to draw the modified cartoon for Bruce in two dimensions, without much success. Then modelling clay came to the rescue and I was able to show him what I meant.

So I would like to share the 3D modelling clay version, but before we look at the breakage-fusion-bridge cycle, which is an abnormal pattern of chromosome division, we had better look at normal chromosome division (or mitosis).

These are chromosomes in modelling clay. There are 23 pairs of chromosomes in a human cell but we will follow 3 chromosomes for simplicity. The chromosomes only take on a recognisable shape when the cell is ready to divide. Each chromosome is made of two halves called chromatids, which are identical. These are held together at the centromere.

In a cell the chromosomes are usually not recognisable – the DNA is unravelled in the nucleus. In a growing cell each unravelled chromosome is producing a copy of itself so that there will be a chromosome for each of the two new daughter cells when the cell divides, or reproduces itself.

After the chromosomes take shape they line up together (at the metaphase plate) between two ends, or poles, of the cell. The centromere has another very important function in cell division. It attaches to fine fibres (microtubules) which stretch between the poles.

The two halves of the centromere separate and each draws its chromatid (which is now a new daughter chromosome) along these microtubules.

So when the cell divides in two to make two new cells, each chromatid becomes a chromosome in one of the new cells.

Cell division complete, the chromosomes unravel and copy themselves again ready for the next cell division.

This process happens successfully millions of times every day to create new cells in our bodies – amazing.

In the year 2000 the draft human genome sequence was announced by Tony Blair and Bill Clinton. It was said to be complete in 2003, in time for the 50^th anniversary of the discovery of the structure of DNA. Well actually it wasn’t quite finished. Actually it’s still not finished. Besides the tweaking that still goes on here and there, there are still big gaps. And what’s in these gaps sometimes has a significant role in cancer.

The biggest gaps are centromeres. Centromeres and telomeres are made of what is known as repetitive DNA, and this is hard to sequence. There’s more detail below.

Cancer chromosomes often have centromere or telomere abnormalities. In fact these abnormalities can cause cancer or make it progress faster.

In cancer research there’s a big push to sequence the genomes of different types of cancer to try and understand the many different DNA changes that can cause cancer. Some researchers try to understand telomeres and centromeres and their role in cancer, but in cancer sequencing projects, and also in diagnostics, centromeres and telomeres are pretty much ignored. Although they’re difficult to sequence, the repetitive DNA does make them easy to study by some other techniques.

One of the goals of personalised medicine is to be able to read a person’s complete genome. For cancer this would include the abnormal cancer genome. But at the moment these gaps mean that we can’t describe the abnormal cancer chromosomes from end to end by sequencing them. The approach I use allows me to work out what’s in each chromosome and discover telomere and centromere abnormalities.

HOW DOES MY RESEARCH FIT IN?

By looking at things that most people don’t worry about I’ve overturned a few assumptions and made some unexpected discoveries, particularly about centromeres in leukaemia.

A normal chromosome has one centromere. I found that chromosomes with two centromeres are more common in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) than was thought. I found that most of these chromosomes with two centromeres were probably made by two chromosomes joining together.

Telomeres are at the ends of chromosomes and stop them from sticking to each other, so when the telomeres are eroded, chromosomes can join together. They can be eroded by exposure to chemical toxins, cancer drugs and radiation. So it’s interesting that the leukaemias that are caused by these exposures have more of these two-centromered chromosomes than other leukaemias.

Fluorescent DNA probes can label up centromeres (blue) and genes (red). In this image there is also a chromosome 20 paint – the green regions are from chromosome 20.

MORE DETAIL ON THE SCIENCE

Telomeres and centromeres are made of highly repetitive DNA and make up some of the gaps in the human genome sequence.

Sequencing a genome is like reading a story. But first we cut the book up into tiny fragments. We read them piece by piece, then try to join the pieces together to make the story, by matching the overlapping parts. Where this approach falls apart is that some sections are repetitive. Some pages are made up of a single word or phrase repeated over and over and over and over and over and over (I won’t repeat that hundreds of thousands of times, but you should get the picture). So if a lot of fragments just say the same thing “over and over and over”, it’s very hard to put them together meaningfully.

The centromere guides the chromosome to the two daughter cells during cell division. A normal chromosome has one centromere. When a chromosome has two centromeres (we call this a dicentric chromosome), the chromosome can be pulled in opposite directions, breaking the chromosome and causing more chromosome disorganisation.Telomeres cap the ends of normal healthy chromosomes. One of their functions is to stop the chromosomes from sticking to each other. So when the telomeres are lost or eroded the chromosomes can join together. That’s one way of creating a chromosome with two centromeres.

Telomere loss is a natural part of ageing. There are also many environmental and lifestyle factors that are thought to affect telomere length. Short telomeres are thought to be a cancer risk because dicentric chromosomes are more likely to arise.

Telomeres and centromeres are very important parts of a normal chromosome. You could say they hold the chromosome together. They have a lot of influence on whether chromosomes are normal and stay normal.

Art meets Science: demonstrating chromosome division

The last frontier of the Human Genome Project – repetitive DNA.