Mistakes in the members

Mistakes in the menders: mismatch repair and cancer

We all know that cancer could affect any of us at any time. Many of us try to decrease our risk of cancer by sticking to a healthy lifestyle, fruit but one thing we can’t do anything about is our genes. Sadly, some people are just born with a higher probability that they will get cancer. And yet there is hope; learning about the genes and cellular processes that cause a high risk of cancer can help progress toward earlier diagnosis and improved treatments.

What does it mean to inherit a high risk of cancer?

There are some, thankfully quite rare, changes in important genes that cause a high chance of getting cancer. Hereditary Non-polyposis Colorectal Cancer (HNPCC) (also known as Lynch Syndrome) is one of these so-called cancer pre-disposition syndromes. Colorectal cancer normally only affects people later in life – over the age of 60 – but people with HNPCC are often diagnosed with this cancer in their 40s and 80% of individuals with this syndrome will get colorectal cancer during their lifetime. As well as colorectal cancer, HNPCC also causes an increased risk of tumours in other parts of the body, such as the lining of the womb (the endometrium) in women.

So what causes HNPCC?

People with HNPCC are born with a defective copy of one of several genes that are important for preventing mistakes in DNA: pregnant the DNA mismatch repair genes. You inherit two copies of all your genes – one set from your mother and one from your father. Often one defective copy of a gene can be compensated for by the fully functioning second copy, but not always. Genetic defects that cause a clinical condition when just one defective gene is inherited are called ‘dominant’; HPNCC is one such condition. This means that most people with HNPCC will have a parent who also has HNPCC.

Why do problems with mismatch repair genes cause cancer?

Tumours form when a cell in the body starts to grow out of control. Normally, how often a cell divides to form new cells is very tightly controlled and the new cells will be programmed to function correctly for the part of the body that they are in. But a tumour cell divides very rapidly and doesn’t follow a programme. Because the instructions for a correctly functioning cell are written in its DNA, changes in DNA lie at the heart of cancer. Problems with the mechanism that a cell normally uses to protect its DNA from mistakes will mean that there is a much higher chance of errors in the genetic instruction manual. This means a much higher chance that a cell will behave abnormally and will start to grow into a tumour.

Which genes are involved?

Mismatch repair is a complicated process: different proteins are needed for spotting mistakes in DNA, cutting out the incorrect DNA letters, and replacing them with a perfect genetic code. Therefore it is not surprising that there are several genes that – if they have a mistake in them – cause HNPCC. The most common cause of HNPCC is a mutation in a gene called MSH2, which is important for recognizing errors in DNA. Scientists are working to find out more about the part played by this gene and the others that can cause cancer when they don’t work properly.

If mismatch repair happens in all cells, why do defects in mismatch repair genes make cancer more likely in some parts of the body? This is a puzzle that scientists are still trying to work out. Because mismatch repair is really important when cells divide – because this is when DNA is copied and mistakes can be made – it might be that that cancer is more likely in parts of the body where cells are dividing more often. Digesting food is quite a labour-intensive business for the body and cells in the colon are continually being replaced by new ones. This might mean that the colon is particularly reliant on a fully functioning mismatch repair system.

How does knowing about mismatch repair help?