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Wilms’ tumour and the WT1 protein

Most of the time, cancer is a disease that affects older people. Mutations and damage to our DNA happen throughout our lifetime and add up as we age. The longer we live, the more mutations we accumulate, and these can increase our risk of developing cancer.

But sometimes cancer is caused by mutations that we are born with. Around 1,800 children are diagnosed with cancer each year in the UK, and most of these cases are due to mutations present at birth. A cancer diagnosis in someone so young can be devastating for their families and loved ones, but the good news is that, thanks to research, around three-quarters of these children now survive.

Worldwide Cancer Research has funded research into a wide range of childhood cancers. Wilms’ tumour, a rare type of kidney tumour usually diagnosed in children under five, is one example.

Wilms’ tumour

Wilms’ tumour was named after Dr Max Wilms, following his work on this childhood kidney cancer. It is thought to start from immature kidney cells in the developing embryo in the womb.

Usually these immature cells mature by the time the child is three or four, but in many children with Wilms’ tumour, clusters of underdeveloped kidney cells, called nephrogenic rests, can still be found, and they begin to grow out of control into Wilms’ tumour. The most common symptom is a swollen, but painless, abdomen (tummy) and there may be a lump in the abdomen.

In most cases, the cause is unknown but a small number are due to genetic factors including faulty genes like WT1 (Wilms Tumour 1).

WT1

The WT1 gene acts as a tumour suppressor, which means that when it is working properly, it stops tumours from forming. It also makes the WT1 protein, which sticks to DNA and switches key genes off and on. Mutations to the WT1 gene, which stops it making the WT1 protein, causes a small proportion of Wilms’ tumours.

Professor Stefan Roberts used his Worldwide Cancer Research grant to show that another protein called BASP1, is essential in helping the WT1 protein regulate the switching off and on of genes. After these findings, Professor Roberts obtained grants from several other funding bodies, and he continues to study WT1 and BASP1, more than ten years later.

Back in 2002, we gave Dr Michael Ladomery his first grant, which enabled him to set up his own research group/lab. They found that the WT1 protein sticks to something called alpha-actinin. Alpha-actinin is involved in controlling the cell’s internal framework, used to keep the cell’s shape. This is particularly relevant to cancer, because cancer cells often have an abnormal shape and structure, so changes that affect WT1 protein or alpha-actinin might play a role in cancer-causing changes to our cells. To this day, he is continuing his research into RNA and mRNAs.

Could other genes be involved in causing Wilms’ tumour?

Over the last 30 years, we have spent more than £1 million on ten projects studying Wilms’ tumour and the WT1 gene. But Wilms’ tumour is often caused by mutations in other genes; scientists have also studied other causes of the disease.

Professor Michaeala Aldred, from the Cleveland Clinic, USA, studied a rare genetic condition called 2q37 deletion syndrome, which can cause a range of different syndromes; a small number of children are also more likely to develop Wilms’ tumour. She was able to narrow down the region on chromosome 2, which contributes to Wilms’ tumour. This is helpful to parents of children diagnosed with 2q37 deletion syndrome, since their doctors can give more informed advice about the possible risk of their child developing Wilms’ tumour. Children who do not have the genetic fault that can lead to Wilms’ tumour can avoid regular tests to check for the disease. Knowing that their child won’t develop Wilms’ tumour is also a likely relief for parents.

In addition, Professor Aldred found that the DIS3L2 gene is located within this region of chromosome 2. At the same time, Professor Eamonn Maher at the University of Cambridge was also studying Wilms’ tumours, with help from a separate Worldwide Cancer Research grant. Professor Maher discovered that this DIS3L2 gene causes Perlman syndrome, a condition that can increase a child’s risk of developing Wilms’ tumour. We hope this discovery will enable even more effective diagnosis and treatment of Wilms’ tumour.

WT1 in other diseases

While the presence of WT1 helps to prevent Wilms’ tumour, conversely, WT1 has been shown to play a part in causing the development of several adult cancers, such as leukaemia and breast cancer. With our funding, Dr Aswin Menke was studying the role of the WT1 gene in leukaemia, by investigating its role in normal blood development and in leukaemia. Dr Menke’s findings, and that of others, confirmed that WT1 could be a useful way to direct the immune cells to kill leukaemia cells, a treatment known as immunotherapy.

A number of clinical trials have been carried out to test whether our immune system can be retrained and manipulated to kill leukaemia cells, for example by hunting down and killing leukaemia cells with the WT1 on their surface. However, as WT1 is often present on non-leukaemia cells it is necessary to avoid immune cells from attacking WT1 in healthy cells, as this would have severe side effects for the patients. We funded Professor Hans Stauss’ work, which he used to show that it was possible to use T-cells (a type of immune cell) to specifically kill leukaemia cells that expressed the WT1 protein (without affecting healthy cells), meaning a better potential new treatment for these patients, with fewer side effects.

It didn’t work for cancer, but could be of great benefit for kidney patients

Sometimes great things come from negative findings. For a while scientists thought that a technique called RNA interference might be the way forward in treating Wilms’ tumour. Professor Jamie Davies and his colleagues debunked this idea, but, whilst working on it, they invented a technique for kidney tissue engineering. This has nothing to do with cancer, but it has obvious medical potential, and the Medical Research Council (MRC) are now generously supporting this work.  Professor Davies told us:

“In effect, that work - which may one day result in lab-engineered kidneys for people - was triggered by findings from the Worldwide Cancer Research grant. This was a very significant project for my group.”

Much of the research we have funded over the years on Wilms’ tumour has been to help better understand the genetic cause. This is vital to find new ways of preventing, diagnosing and treating the disease and saving the lives of more children in the future.

 

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