Radhika Holmstrom reports on the latest genetic research going on into Uveal Melanoma.
“For a lot of patients, there is a shock that the eye is involved in cancer. You don’t think you can get cancer in the eye,” says Dr Karen Sisley, who is a senior lecturer at the University of Sheffield.
In fact, around 600 to 700 people in the UK develop a uveal melanoma every year – far more than the number of people (usually children) who present with retinoblastoma, the inherited eye cancer. Like most cancers these are more prevalent in people over 50; and like skin melanomas, they develop from the melanocyte cells which give the skin its colour and are more common in people with pale skin and/or eyes. However, these melanomas appear to have no link with sun damage and they are the result of different cellular mutations, with completely different genetic portraits and completely different behaviour from skin melanomas.
“You can classify uveal melanomas into the anterior ones, affecting the iris; the posterior tumours affecting the ciliary body; and those in the choroid,” Sisley explains. “The ones that have the worst prognosis are the ones from the posterior, and of those the ones in the ciliary body have the worst of all. Broadly speaking, they have different genetic changes as well.” (A few people – though this is much rarer – develop a melanoma in the conjunctiva, which is again slightly different from those in the uvea.)
Uveal melanomas do affect the vision to some degree – the symptoms can include blurred vision, changes in the field of vision, flashers or floaters in the eye – but most people are only picked up at a routine eye examination, before being sent for a more detailed diagnosis and possibly (though not always) a biopsy.
There are four centres around the UK (in Glasgow, Liverpool, Sheffield and London) which specialise in uveal melanoma.
The full range of treatments include cryotherapy (freezing) transpupillary thermotherapy (heating by laser), proton beam therapy and photodynamic therapy as well as surgery, radiotherapy and chemotherapy. Some people do undergo ‘enucleation’ – removal of the entire eye – if the tumour is too large to treat otherwise, and/or it is affecting the macula. However, other people retain the eye, along with some degree of vision.
“The success rate for treating primary tumours is very high,” says Professor Sarah Coupland, director of the North West Cancer Research Centre - University of Liverpool, which also provides ‘local resection’, where only the tumour is removed. “It’s the treatment of the metastases which is very difficult.”
As Coupland flags up, the huge problem with uveal melanoma is usually further down the line; for about half the patients, the cancer metastasises – establishes new tumours in a completely different part of the body. Whereas skin melanomas usually metastasise through the lymph system, uveal melanoma usually does so via the bloodstream. And the new tumours are typically in the liver, which means that the average survival rate is very poor indeed. Standard chemotherapy isn’t usually effective. It is sometimes possible to remove the tumour surgically while leaving the liver still able to function. There are also new therapies like ‘chemosaturation’, where the blood supply to the liver is isolated, so that it can receive a very high dose of targeted chemotherapy medication. Some clinical trials are exploring other forms of ‘systemic’ chemotherapy (which goes through the entire bloodstream). However, most people do not live longer than a year at the most after their new tumour has been diagnosed.
On the other hand, research into the genetics of ocular melanoma has uncovered some of the changes that cells undergo. “We and others have demonstrated that if you can stratify the tumour cells into ‘good’ melanoma, who are highly likely not to develop metastases – and those who have ‘bad’ ones,” says Coupland. “People with alterations on chromosome 3 and 8 almost always develop these metastases.”
Sisley explains some of the detail. “Compared to other cancers, there are certain ‘hot chromosomes’ which are consistently involved. We’ve been identifying genetic changes that could have a clinical significance since 1992 and found relevant chromosome alterations in the early studies, involving chromosomes 3, 6 and 8. Then in 1997 a German group in 1997 established that the loss of chromosome 3 is related to poorer survival. Around the same time, we found that if patients whose melanoma lost chromosome 3 and gained material from chromosome 8 at the same time had a bad prognosis with a shorter survival. Since then other changes of chromosome 1 and 6 have been identified as clinically relevant as well.”
This means it is now possible to offer genetic testing – but of course that brings its own dilemmas; it’s a roughly equal chance that someone will be told they’re in the clear once their melanoma has been successfully treated, or that they will very probably develop another tumour and die quite quickly. “We give them their individualised prognostic curve,” says Coupland. “The patients with ‘bad’ melanoma then undergo closer and more intense screening of the liver using MRI rather than ultrasound. Some want to do this, and have regular checks. Others prefer not to know.”
Coupland, Sisley and many others are now trying to unpick the genetics further, with the aim of being able to find ways of intervening in the process. At Sheffield, where Sisley leads the laboratory research into uveal melanoma, she and her colleagues are developing a bank of uveal melanoma cell lines, which will make it possible to compare and contrast the essential differences and use the information to improve the understanding of these tumours. A number of new cultures have already been established, several have undergone full genetic characterisation, and the first research project based on these cell lines is due to start in mid-2016. As with other cancers, the ultimate aim is to come up with personalised treatments targeted to each person’s genetic changes.
Some of this work is looking at the gene changes that happen further down the line. At the moment, the focus is usually on the initial ‘switches’ in the hot chromosomes. It is pretty clear, though, that other switches happen at a later stage and that these are crucially involved in producing the metastases. Coupland is exploring a gene called BAP1, which is ‘switched off’ in around 80 per cent of the uveal melanomas that metastasise. “We don’t completely understand the metastatic process yet. When we have had the possibility of examining tumours in the liver for BAP1, half do and half don’t express BAP1. If you have BAP1 positivity in the nucleus of the cell, this correlates to a normal status of chromosome 3. If you have BAP1 negativity, typically you have a higher risk,” she explains. “Some patients have this mutation throughout their bodies (it’s called ‘germ line BAP1’) and these people are at risk of developing all kinds of other tumours – but this is incredibly rare. In most cases, these mutations are occurring in the tumour cells and the tumour cells only.”
At the moment, a diagnosis of uveal melanoma heralds a very difficult level of uncertainty – to test or not to test? Will this be relatively straightforward, will it involve losing an eye, and/or will it result in an untreatable tumour on the liver? – but there is a huge amount of research into the condition. “At our centre, we’re involved in a multi-centre research project being funded by the EU; a consortium looking at metastatic uveal melanoma, and we are looking at various animal models and with two pharmaceutical companies as well, with the aim of getting to clinical trial stage,” Coupland points out. “It’s a very large gene and a lot of people are working on it.”