Bob Marley, genomics, and a rare form of melanoma

In May 1981 the music world lost a legend when reggae artist Bob Marley died after a four-year battle with a melanoma skin cancer that started on his toe.

This may seem strange, as melanoma is usually associated with fair skin and exposure to UV radiation from the sun. But in fact Marley was diagnosed with a rare but fast-growing type of skin cancer known as acral melanoma, which isn’t strongly linked to UV exposure.

Named after their location – the hairless acral skin on the palms of the hands, soles of the feet and under the nails – these tumours are very different from the majority of melanomas that arise elsewhere on the hairy bits of the skin, which are known as ‘cutaneous’ melanomas.

There are a couple of other unusual types of melanoma – ocular (uveal) melanomas that grow in the eye, and mucosal melanomas that start on the mucus-producing surfaces of the body, such as in the mouth or up the nose. These are also much rarer than cutaneous melanoma.

What ties these tumours together and makes them all melanomas is that they each arise from rogue pigment producing cells found in the skin called melanocytes. The pigment they produce, melanin, is mainly responsible for skin and hair colour, and helps to protect us from UV rays from the sun.

But while their biological roots may be the same, there are key differences between them, affecting how they grow and spread in the body, and how they respond to treatment.

So to find out more about these unusual cancers – and work out how best to approach treating them – our researchers at the Manchester Cancer Research Centre, led by Professor Richard Marais, have been delving into the world of genetics.

Different gene faults

When Bob Marley died in the 80s, the sort of genetic analysis techniques now available to Professor Marais and his team would have seemed like something out of Back to the Future.

Modern advances in researchers’ ability to analyse, or ‘sequence’ DNA are revolutionising our understanding of many types of cancer. It’s now possible to ‘read’ all the genetic information within the cells of a tumour (its genome) in a matter of days, revealing the catalogue of gene faults they carry.

And in a new paper published in the journal Pigment Cell & Melanoma Research, Professor Marais and his team have looked in detail at the genomes of acral melanoma samples taken from five patients. They bolted this on to information from three other acral melanomas they had previously analysed (making eight in total), and compared the findings with data from five mucosal, 12 uveal and 25 cutaneous melanomas.

Their analysis revealed that the genetic faults in acral melanoma are very different from these other types of skin cancer.

The DNA in cutaneous melanoma is characterised by tens of thousands of ‘typos’ in the DNA code – individual single changes scattered around the cancer’s DNA. In contrast, most of the acral melanomas had fewer of these single letter genetic faults. Instead, large chunks of DNA had broken off and reattached elsewhere – a bit like large sections of text being randomly cut and pasted throughout a document. Other sections were missing altogether.

Homing in on specific genes, the researchers discovered that these distortions in acral melanomas led to mutations in several of the ‘usual suspects’, which have also been implicated in other types of cancer. These include genes called BRAF and KIT, which are already known to be faulty in cutaneous melanoma.

Professor Marais and his team also spotted a selection of other faulty genes in various acral melanoma samples, including mutations in genes called p53, PTEN, NRAS, and APC – all of which are well-known culprits that can cause cells to grow out of control, leading to cancer.

So what makes these tumours distinct?

What causes different melanomas?

The researchers also uncovered some intriguing information about the potential causes of different types of melanoma. It’s been known for some time that cancers on hairy skin carry the characteristic hallmarks of damage wrought in their DNA by ultraviolet (UV) rays from the sun or sunbeds. It’s also clear from large studies that UV is a major risk factor for these tumours.

But although Professor Marais and his team previously found evidence of this kind of DNA damage in a sample taken from an acral melanoma patient a couple of years ago, and in cells from acral melanomas grown in the lab, the acral tumour samples in this latest study didn’t have the hallmarks of UV damage. This suggests that while UV exposure may play a role in some patients’ acral melanomas, it’s not a major driving factor.

The other interesting finding from their analysis is that acral and mucosal melanomas seem to be broadly similar when it comes to the amount and type of genetic damage – with both having less than cutaneous melanomas – while uveal melanomas are different again. These eye cancers seem to have particularly low levels of genetic chaos within them, and the faults they do have probably come from a different source.

Moving away from ‘one size fits all’

In the world of music it would probably be seen as over simplistic to group all artists under one umbrella. Even within reggae-based music pioneered by Marley and other artists, there is a plethora of genres from roots to rockers, dub to dancehall.

As we’ve written about before, in the world of cancer research and therapy we’re moving away from a ‘one size fits all’ approach to how we target the disease, focusing instead on the underlying genetic makeup of an individual patient’s disease.

This research, and more like it going on around the world, is prising open the ‘black box’ of cancer and challenges us to think in a new way. Understanding the individual genetic faults driving different types and subtypes of cancer is key to treating it more effectively in the future.

In particular, finding out about the specific faulty genes that drive different types of melanoma is vital for finding more effective ways to treat these aggressive diseases. For example, the drug vemurafenib (also known as Zelboraf) targets faults in the BRAF gene, and other such gene-targeted therapies are in development.

But this isn’t without its challenges. We’re now finding out that cancer’s genetic complexities can vary throughout a patient’s body, and even within the same tumour. And these faults can also change and evolve as the disease grows, helping it develop resistance to treatment.

There’s also a lot of work to be done to figure out how best to use new genetically-targeted therapies to improve survival (something we’re starting to do in our new Lung Matrix Trial). And given the recent headlines about the cost of cancer drugs, this is clearly a political and financial challenge as well as a scientific one.

But with every new research paper, we’re building a growing map of this complex set of diseases that we call cancer. And we believe that it will lead us to new cures that can make a difference to patients everywhere.

Kat