Creating a national Lynch syndrome registry

Lynch syndrome is a genetic condition that increases the lifetime risk of bowel cancer to up to 80%. As part of a research project we funded, and along with colleagues at Newcastle University and Health Data Insight CiC, Dr Fiona McRonald from Public Health England is working to create a national registry of people with Lynch syndrome. It’s hoped this research will help inform surveillance, treatment and care of people with the condition. Dr McRonald tells us about her career so far and the importance of this research for those with Lynch syndrome. .

Could you tell us a bit about your research career to date?

From a young age, I’d always been fascinated by genetics and human diversity, so I studied medical science at University, and specialised in genetics. I clearly remember reading a scientific paper about DNA within cancer cells, and having a bit of a revelation: for the first time, I truly understood that DNA mutations within individual cells are the fundamental cause of cancer.

The 1990s was a tremendously exciting time to be studying genetics – the Human Genome Project was well underway, and lots of genes and mutations were being identified and linked to diseases. After setting up a research registry of families with hereditary pancreatitis and/or pancreatic cancer, I trained as a genetic counsellor – I qualified in 2001; just as the draft sequence of the human genome was published!

For my PhD, I joined a small research team mapping the gene associated with a rare inherited condition called tylosis with oesophageal cancer. By this time, it was apparent to me that I wanted to continue working on rare inherited cancers – if we could identify people at high risk of developing cancer, there was so much we could do to screen for tumours and detect them at an early, treatable stage – ultimately, we could save lives in the families most vulnerable to cancer.

In 2015, I was delighted to join Public Health England to set up a genetics data programme within the National Disease Registration Service and the National Cancer Registration and Analysis Service (NCRAS); this is how I got involved with this cutting-edge piece of work on Lynch syndrome.

What is Lynch syndrome?

Lynch syndrome is an inherited condition that causes susceptibility to certain cancers, including bowel cancer. People with Lynch syndrome have inherited a variant in one of four similar genes known as mismatch repair (MMR) genes. As the genetic change is inherited, it’s present in every cell of the body (we call this a germline mutation), which is why the person has a high chance of developing cancer.

The normal job of MMR genes is to correct DNA mistakes or ‘typos’ that occur when DNA is copied in preparation for cell division. When an MMR gene stops working, DNA is not repaired properly, so lots of mutations will accumulate. Many of these mutations are harmless, but some can cause the cell to grow in an uncontrolled way – i.e. the cell becomes cancerous.

Why is it important to have a registry for Lynch syndrome? 

It’s crucially important to have a registry for Lynch syndrome. We now think that Lynch syndrome is much more common than was initially assumed – so not all families will be on the radar of NHS genetics services; this means that these people are not being offered the additional screening to which they are entitled. At NCRAS, we already know about every case of cancer diagnosed or treated within the NHS – that’s a lot of important data!

By comparing tumour data from people known to have Lynch syndrome with the other data we hold, we might begin to see patterns within groups of people who might have Lynch syndrome, but have not yet been identified. The registry will also help geneticists to provide more personalised information about cancer risk and surveillance to individuals with Lynch syndrome.

One of the big challenges for geneticists is how to tell the difference between a damaging gene variant causing Lynch syndrome, and a harmless change in the gene. We all have sequence variants in our DNA – this is what makes the human species so wonderfully diverse – and the vast majority of these changes are not harmful. The process of ‘variant interpretation’ relies on multiple threads of highly technical evidence; for this to be successful, it’s crucial that geneticists share knowledge and data with one another.

At NCRAS, we’re in a unique position to be able to collect all NHS data on MMR gene variants, in a way that protects the patient’s identity, but enables the data to be linked to their cancer registration record. We can then count the number of times each particular DNA sequence variant has been identified in an NHS lab, and share this anonymised information with a specialist committee of NHS geneticists. Having access to this data from across the whole country means geneticists can give patients more accurate information and advice about their gene variant.

How far have you got with this project?

So far, we’ve built the secure data-sharing technology and collected MMR gene data from four large NHS labs; other lab submissions are in progress. It’s a complex piece of work just to process each lab’s data and standardise it into a consistent format before we can count the DNA variants. It’s a real privilege to work with some brilliant IT and bioinformatics colleagues to achieve this – a great example of several sciences coming together to solve a complex problem. 

What’s next? 

We’ll release the MMR gene variant counts back to the NHS geneticists later this year, so that they can review and interpret the data. Once each variant is classified as harmful or benign (harmless), genetic counsellors can update affected families on their cancer risk and options. It’s incredibly rewarding to be doing work that could benefit some families with bowel cancer in just a few months’ time. A huge “thank you” is due to Bowel Cancer UK and its supporters for funding this work!

• Find out more about this research project

• Read more about Lynch syndrome
  

• Find out about our Time to Test for Lynch syndrome campaign