In the two previous chapters I outlined the key science underpinning skin cancer susceptibility. UVR damages DNA but DNA repair is imperfect and therefore mutations accumulate. And melanin acts to protect against this process. If we now add in some ‘common sense’ facts we can build a complex map of susceptibility  that guides our clinical behaviour. We can, to use the cliché,  move from bench to clinic. Let us see how these predictions work out.

Age

Age is a proxy for exposure to UVR, in that on average, older people will have had more UVR exposure — simply because they have been on the earth longer. Older people will therefore  have accumulated more mutations.

We therefore expect skin cancer rates to rise with age — which is of course what we do see. It is not therefore the ‘age of a patient per se’, but merely the fact that age is a marker of cumulative or lifetime UVR exposure (and damage).

Ambient exposure to UVR

If UVR is the main cause of UVR, then the epidemiology of skin cancer must be strongly influenced by the patterns of exposure to UVR. This will include the ambient UVR, and the relation between different body sites and ambient UVR.

mage on left: Australia_(orthographic_projection).svg: Ssolbergj
derivative work: Roke (talk) – Australia_(orthographic_projection).svg, CC BY-SA 3.0, Link

People living in areas with high ambient UVR will —all other factors being equal—have higher cancer rates. We therefore expect skin cancer rates to be higher in those living close to the equator. We can unpack this further. If people migrate to a sunny climate later in life, their childhood exposure will likely have been less, and therefore their rates may remain lower than those brought up in their adopted land.

Whatever the ambient UVR, different body sites are exposed differently. The scalps of bald headed men, the backs of the hands and the tops of the ears receive more UVR than say the buttocks or even the back or legs.

There are some details that may not be obvious. Traditionally, the tops of the ears of men receive much more UVR than the equivalent area of women — hair is more likely to cover the ears in women than men. Therefore, in some populations, we see melanoma rates are 3-5 times higher on the tops of the ears of men than on women. If the fashion for some young men to shave their scalps continues, you can work out what might happen. Those ageing hippies with their long hair were perhaps onto something…..

Human behaviour

Although the amount of ambient UVR is one factor, individual behaviour in the sun is also critical. Do you spend much time at the beach ?

The more clothes that are worn, the lower the dose the skin receives. If you are bald, but wear a hat, the effective UVR dose is diminished. If you have hobbies or work in an occupation that increase exposure (e.g. surfing, fishermen), expect UVR exposure to increase. Again, the permutations may not be obvious. There is indeed more UVR in Brisbane than Glasgow, but a child addicted to computer games in Brisbane may receive less UVR than a child in Glasgow who spends much of their leisure time playing football.

Pigmentary phenotype

The previous chapter highlighted how important pigment in preventing against UVR damage and skin cancer. The less eumelanin there is, the less protected skin is. Dark skinned Africans are over 100 times less at risk than pale skinned north Europeans.

But there is still some uncertainty in our knowledge. Those with red hair for instance tend to have paler skin that those without red hair. Their skin also tends to be paler and have less eumelanin, and possibly more pheomelanin either in absolute terms or relative terms (their hair certainly has a higher amounts of pheomelanin). There is however still uncertainty (and debate) about whether it is the absence of eumelanin that is the chief problem, or whether pheomelanin is not only not very protective, but positively harmful if exposed to UVR. Whatever the exact mechanism, those with red hair or those with a phenotype characterised by more pheomelanin in their hair, are at increased risk of skin cancer. This phenotype is characterised by not only red hair, but abundant freckles (focal areas of overproduction of melanin). Freckles reflect both UVR exposure and the underlying pigmentary phenotype.

Images with permission of Reto Caduff. Link.

Genetics: Mendelian

We have mentioned the contribution of genetics on several occasions. Xeroderma pigmentosum is an autosomal inherited disorder characterised by an inability to repair UVR induced DNA damage, so cancer rates are increased. Albinism is again a group of (autosomal recessive) inherited disorders characterised by a reduction in the amount of melanin, and hence increased cancer rates. The disability will of course reflect the type of albinism and UVR exposure: an albino living on the equator will more likely come to harm than one living in Finland. And, as just discussed, those with red hair, a trait under the control of the melanocortin 1 receptor, which approximates to a Mendelian recessive trait, are at increased risk of skin cancer.

Image: Bolzer et al. PLoS Biol 3(5): e157 DOI: 10.1371/journal.pbio.0030157

There is one other group of Mendelian disorders, that we have not mentioned but we need to briefly highlight, namely inherited tumour suppressor syndromes.

Mutations of tumour suppressor genes

Some genetic change is dominant at the cellular level in that only one allele is required to be mutated for an effect to be seen. By contrast, tumour suppressor genes are recessive at the cellular level. This means both alleles (one on the paternal and the other on the maternal chromosome) need to be inactivated for an effect to be seen i.e. two ‘hits’ have to occur

Although both changes (two hits) can occur due to UVR it is possible to inherit a mutation on one allele and for the second genetic change (‘hit’) to occur due to UVR at a later time on the other allele. This is known as the Knudson two hit hypothesis and predicts that if a person inherits a germline mutation in a tumour suppressor gene, tumours will occur at a younger age due to only one more hit being required to advance to the next stage of carcinogenesis. It is also implicit in this model, that the chance of one individual acquiring multiple tumours if they have inherited a germline mutation is also increased. In some cases involving the skin, a single patient might have hundreds or rarely even thousands of skin cancers.

The practical point is that some inherited syndromes involving tumour suppressor genes may lead to some types of skin cancer, and that most typically such individuals will get many tumours at an earlier age than otherwise expected, and that there may be multiple primary tumours. Some cases of melanoma are familial and are due to mutations in tumour suppressor genes, as are some cases of basal cell carcinoma (so called Basal Cell Nevus Syndrome also known as Gorlin’s syndrome). We will discuss the clinical aspect of these syndromes later in skincancer909.

Genetics: complex

Finally, although I have not specifically mentioned it, skin cancer susceptibility is also genetically complex. The degree of melanin pigmentation is a major risk factor, and variation is skin colour reflects the effects of a large number of genes (hence complex). Everyday common sense tells us that skin colour variation is under genetic control but that it does not follow the strict rules of Mendelian inheritance.

There are other traits that likely influence skin cancer susceptibility, although they have been less well studied. We know for instance that there are modest differences in DNA repair between people, likely the result of variation at some or many of the genes that code for enzymes involved in UVR induced DNA damage. There may well be other factors not discovered, too.

Skin cancer: more than the accumulation of mutations

The theme I have used to explain skin cancer is that the accumulation of mutations leads to the cancer phenotype, and than anything that increases DNA damage (such as pale skin) will increase cancer rates. There is however one important bit of the skin cancer jigsaw that this model is missing: the role of the immune system.

The skin is an immunological organ, acting both is a sensory capacity, and as an effector wing (i.e. as a target). The epidermis contains Langerhans’ cells — professional antigen presenting cells — and the dermis contains many other types of immunological cells, including antigen presenting cells. In addition the epidermis contains occasional T cells. Although the details are unclear, the critical role of he immune system in human cancer, is largely based on clinical observations of what happened to patients who had receive organ transplants.

Increased rates of skin cancer in organ transplant recipients

Patients who have undergone allogeneic organ transplants (such as heart, live or kidney) usually require lifelong immunosuppression to suppress donor organ rejection. Soon after the development of renal transplantation, it became clear that the rates of the common non-melanoma skin cancers particularly squamous cell carcinoma was greatly increased. This increased risk is secondary to the immunosuppression these patients receive (although in some instances it may be in part) secondary to some immunosuppressive drugs increasing UVR induced DNA damage e.g. azathioprine).

By Tiiu Sild – Own work, Public Domain, Link. Reconstruction of Dr Barnard’s first human heart transplantation in December 1967

The exact mechanism or mechanisms by which immunosuppression increases skin cancer rates is unclear. One possibility is that immunosuppression might allow certain oncogenic viruses to play a causal role. For instance, organ transplant recipients are at increased risk of cervical and anal cancer, cancers that are caused by oncogenic subtypes of human papilloma viruses (HPV). HPV can infect skin and cause common viral warts, and indeed immunosuppressed patients have increased infections from viral warts. However the known oncogenic HPVs are not known to be oncogenic in skin.

By contrast a rare skin cancer, Merkel Cell Carcinoma, is associated with a viral infection with the Merkel Cell Polyomavirus, and the virus is thought to play a causal role in the development of the cancer (health with in the chapter on Rare Skin Cancers).

Another possibility, involving a mechanism that is better understood in the mouse, is that immune surveillance plays a role. It is widely believed — and there is increasing evidence in man — that the immune system acts against cancerous clones, and is able to recognise them as ‘foreign’, and remove them. In this scenario, suppression of the immune system impairs this anti-tumour immunosurveillance, leading to the increase in skin cancer rates we see.

Questions: Bench to clinic

  1. Which areas of skin receive the most UVR?
  2. How — and why— is ageing related to skin cancer risk?
  3.  Why might global warming increase skin cancer rates in some populations ?
  4. What is meant by sun-sensitive?
  5. What are the clinical features of sun-sensitivity?
  6. What does the melanocortin 1 receptor control?
  7. Why are mutations of some genes recessive at the cellular level, but show a dominant pattern of inheritance in families?
  8. Why do patients with the Basal Cell Nevus syndrome present at a young age?
  9. Name two reasons that some patients with organ transplants have an elevated risk of some skin cancers.
  10. Why is the mechanistic relation between some viruses and some skin cancers problematic?

A PDF  containing the above questions and the answers is here. The video talkover below goes through the questions and answers in greater depth. 

Skincancer909 by Jonathan Rees is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Where different rights apply for any figures, this is indicated  in the text.