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New genetic clues about skin cancer

Wednesday 2 April 2014

“Skin cancer: Genetic mutations 'warn of risk',” reports BBC News today.

The science behind the headline involved sequencing the genetic material of 184 people with a strong family history of malignant melanoma, the most serious type of skin cancer.

The aim was to identify previously unknown genetic variations that may increase the risk of melanoma; information that could possibly have a future role in the early detection of people with a high genetic risk.

The genetic profiling narrowed in on variations in the POT1 gene, a gene involved in the protection of the ends of chromosomes, large bundles of densely packed DNA in cells.

The people involved mostly came from families where:

  • numerous people had been affected by melanoma
  • were individuals that presented with multiple separate melanomas, or
  • had developed melanoma at a very early age, suggesting there could be a genetic link for their cancer

As such the research was a step forward in understanding the genetics of melanomas in people with a strong family history, but the results cannot be applied to all people with melanoma.

It is too early to accurately assess whether there could be implications for treatments or whether screening tests for people with a family history would be a viable option.

This research does not change the most important fact about melanomas. While not all cases of melanomas are preventable, you can reduce your risk by avoiding overexposure to sunlight and artificial sources of UV lights such as sunbeds.

Where did the story come from?

The study was led by researchers from the Wellcome Trust Sanger Institute in collaboration with numerous other internationally based medical and academic research institutions. The first author and many colleagues were funded by the Wellcome Trust or Cancer Research UK.

The study was published in the peer-reviewed science journal Nature Genetics.

BBC News reported the study accurately, and discussed the potential implications of the discovery for screening for the disease in people with a family history of melanoma.

What kind of research was this?

This was a genetic study looking to identify new genetic origins of melanoma.

Melanoma is the most serious type of skin cancer. Some of the risk of developing it may be influenced by the genes that you inherit, or your family history.

The researchers estimate that around 10% of people with melanoma have one first-degree relative previously diagnosed. And that 1% of people with melanoma have two or more first-degree relatives previously diagnosed. A number of gene variations have been identified as increasing the risk of melanoma, but others remain unknown. The current study sought to identify new genetic variants that might influence the risk of melanoma in people with a strong family history.

What did the research involve?

The study looked at 184 cases of melanoma from 105 family lines and sequenced parts of their genetic material looking for genetic similarities that may indicate risk of developing the disease.

The people involved mostly came from families where numerous people had been affected by melanoma, or were individuals that presented with multiple separate melanomas or had developed melanoma at a very early age, suggesting there could be a genetic link for their cancer. 

Some people (16 samples) had their entire genomes sequenced, but most just sequenced the parts that made proteins (called the exome).

Importantly these people did not have any of the genetic variants that are already known to increase the risk of melanoma (mutations in CDKN2A and CDK4). So, from a genetic point of view, it was not clear how these people developed melanoma.

By sequencing their genetic material, the research team wanted to find if they had any variations in common. This might point to undiscovered risk factors or causes of the disease.

Including people from the same family line allowed the team to investigate whether the genetic variations were passed from parent to child, or whether the DNA damage had happened spontaneously within the individual and not passed on.

Participants were recruited from the UK, The Netherlands and Australia.

What were the basic results?

The study identified a handful of new genetic variants passed through some families affected with melanoma.

From this long list, the researchers found some of genetic variations affected a similar genetic area. These affected the protection of telomeres 1 gene (POT1), in some cases causing the loss of function in the protein it coded. Telomeres are sections of DNA at the end of chromosomes (highly organised bundles of DNA) that help protect chromosomes against genetic deterioration.

POT1 variations affected four of the 105 families (almost 4%), and was the clearest genetic variant identified during the research. They tested people without melanoma and found they did not carry the same POT1 genetic variants as those with melanoma.

The implication of this was that disruption in the regulation of telomeres, through these specific genetic variations, could lead to cancer.

The researchers subsequently characterised the nature of the genetic variation in detail, including the different variations on the POT1 gene and the resultant effects on the POT1 protein.

How did the researchers interpret the results?

The researchers state that “as the dysregulation of telomere protection by POT1 has recently been identified as a target for potential therapeutic intervention [in other research], it may be possible that the early identification of families with POT1 variants might facilitate better management of their disease in the future”.


This genetic sequencing study identified rare variations in the POT1 gene affecting 4% of families with melanoma of previously unknown genetic origins. The implication was that this variant increased the risk of developing melanoma. Similarly, early identification of families with POT1 variants might facilitate better management and hopefully prevention of any potential disease in the future. For example the families could be given advice about the importance of limiting UV exposure.

However, the current study has only investigated 184 people and found that POT1 gene variants were present in only 4% of people with melanoma. Study in another sample of people with a family history of melanoma may give a totally different prevalence of this variant. Also, previous research has already shown that other genetic mutations are associated with increased risk of melanoma, and there may be others associated that have yet to be discovered. There is not a single gene variant that gives increased risk of melanoma. So although this research is undoubtedly valuable in furthering our understanding of the possible genetics of melanoma in people with a strong family history, there is still more work to be done.  

The findings by themselves are not of any immediate value to patients. However, as Dr Safia Danovi of Cancer Research UK said on the BBC website: “This is a step forward for people with a strong family history of melanoma, the most dangerous form of skin cancer.”

Dr Danovi also provided a useful reminder that genetics is only part of the equation when considering risk of melanoma; sun exposure is a second and much more easily controlled risk factor, “it's important to remember that, for most of us, avoiding sunburn and sunbeds is the best way to reduce the risk of this disease".

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Skin cancer: Genetic mutations 'warn of risk'

BBC News, 30 March 2014

Links to the science

Robles-Espinoza CD, Harland M, Ramsay AJ, et al.

POT1 loss-of-function variants predispose to familial melanoma

Nature Genetics. Published online March 30 2014