Understanding the genetic basis of melanoma

It’s clear that some people are just more predisposed to getting melanoma with the same level sun exposure than others. Andrey/Wikimedia Commonns

An international study published today in Nature Genetics, has discovered two genetic variants that increase the risk of melanoma.

Melanoma is not the most common type of skin cancer but it is one of the most common cancers that affects young people in Australia. What’s really important about it compared to other skin cancers is that although it’s rarer, most of the deaths from skin cancer are due to melanoma.

If it’s not treated early on, it can get very difficult to treat and often leads to death. Other forms of skin cancer are very unlikely to kill you.

One of the authors of the paper, Stuart MacGregor from the Queensland Institute of Medical Research, explains the research.


Melanomas are the deadliest of all skin cancers and have long been known to be caused by sun exposure.

But some people are more likely to get this type of cancer than others. We’ve been trying to understand why, by studying genetic factors influencing the risk of developing melanoma.

This is very important because identifying the risk individuals have helps ensure early treatment, which is currently what makes the biggest difference for survival.

The study

We took 2000 Australians affected by melanoma and 4000 not affected by it and compared them for half a million genetic variants.

We were trying to look for the genes that were more frequent in people with melanoma to find evidence that those genetic markers were important.

When we did that previously, we found genetic variations that change pigmentation, which leads to increased melanoma risk.

But this most recent work is arguably more interesting because we already knew about the effects of pigmentation and mole count, which help indicate how likely you are to develop melanoma.

Now we’ve identified a couple of new genes, one of which appears to play a role in DNA repair, in particular, where cells are required to correct damage caused by sunlight or UV radiation.

The study sought the genetic basis for melanoma. Apers0n/Wikimedia Commons

The other gene we’ve pinpointed seems to be involved in tumour formation.

Taking out the guesswork

These are new biological pathways, which are being suggested as being important in melanoma. Such roles for genes were previously suspected but there was no hard evidence.

Although it may sound obvious that different aspects of the biology, such as DNA repair would be important in the development of melanoma, we haven’t until now had confirmation from genetic studies about these.

In the past, we’ve taken approaches which tried to pick out what we thought were the best candidates for biological pathways but it turned out that we were really, really bad at picking them.

When studies trying to pick the most plausible pathways based on other cell-based biology was done, it didn’t work very well. There was a lot of early work in cancer genetics on “candidate” genes, which was published but then found not to be reliable.

Estimating risk

In this study, we looked at a large number of genetic markers, which means that by chance you will find something: when you do a million different tests, you get a lot of data that looks significant but is only significant because you tested so many.

So the crucial thing we did to ensure robustness, and that’s why this paper is being published in a top publication, is have it replicated overseas.

We found these results in Australian individuals but we also replicated them in people from the United States and from Europe.

So we took what was already a very large study in Australia and had it tested through other studies. This helps ensure that it is robust but also generalises it to other Caucasian populations in Europe and the United States.

It shows that it’s not it’s not just that sun exposure in Australia that’s at play. Obviously sun exposure is important but it’s clear that some people are just more predisposed to getting melanoma with the same level sun exposure than others and we want to understand why so we can improve screening.

Also, by understanding the biology in much more detail we can create drugs and tailor existing drugs to work better for these people.

What we’re trying to do is get a more refined risk estimate. We can already get a reasonable risk estimate based on skin colour and the number of moles, but our work is trying to refine that estimate.

Family hazard

There are some forms of melanoma that are strongly familial. But those families only account for less than 1% of melanomas in the general population in Australia. Most cases of melanoma are of the so-called sporadic type, people who don’t have that many relatives with the disease.

Our research is talking about is the other 99% of melanoma cases which are not familial.

For this, there’s no single gene you can test to try to predict melanoma - it’s a combination of different genes. So we’re building up a profile of all the different cell genetic sets, which influence risk.

The importance of protection

Although we are trying to identify why some people get melanoma and some people don’t, in terms of public health, it’s still important for people to protect themselves by using suncreen, wearing a hat and doing that all year because in most places in Australia, there’s a reasonable amount of UV radiation around.

So it’s important that people take care in that respect.