What we have learned so far
The preceding chapters have described the basic physiology of skin at rest, and the response to UVR. The role of pigmentation and DNA repair have also been highlighted. From this outline it is possible to predict some of the main risk factors for skin cancer: pale skin, exposure to UVR, agents that damage DNA, and variation in DNA repair. There are however several causes of skin cancer that are not explainable in these terms. To learn about these other pathways we need to briefly explore some other topics.
Inherited cancer syndromes and the two hit hypothesis
The dominant paradigm that has underpinned cancer research for 40 years or so is that cancer arises from the accumulation of genetic changes in a clone of cells. Mutations confer new properties on the mutated cells such that they are better able than their peers to grow (or less likely to die). Other characteristics may also be selected for, such as the ability to evade the host’s immune system or the ability to migrate and form metastases. Patients with xeroderma pigmentosum show increased skin cancer rates because they accumulate mutations faster than normal individuals—the underlying process is the same, it is just that the rate is different.
Many forms of genetic change have been characterised in skin cancers including point mutations, loss of larger pieces of chromosomes (deletions) and duplication of genes and even whole chromosomes. UVR can cause point mutations directly and contribute to other genetic changes indirectly .
Some genetic change at the level of the cell is dominant in that only one allele is required to be mutated for an effect to be seen, whereas for genes that are classed as tumour suppressors , the changes are recessive. For the latter group, this means both alleles (one on the paternal and the other on the maternal chromosome) need to be inactivated i.e two hits have to occur
Although both changes 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. 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. Note that although at the cellular level the defect is recessive (both alleles need to be inactivated) at the level of family studies, the disorder will appear to be inherited as an autosomal dominant.
The practical point is that some inherited syndromes involving tumour suppressor genes may lead to some types of skin cancer, and that typically such individuals will get many tumours at an earlier age than otherwise expected.
The role of the immune system in skin carcinogenesis
Genetic change is necessary for carcinogenesis but cancers develop within a particular pathological milieu, and factors external to the clonal tumour influence carcinogenesis. One aspect of the milieu that a cell finds itself in is provided by the immune system. Abundant evidence in the mouse shows that the immune system can play a role in immunosurveillance of skin cancers. Indeed exposure to ultraviolet radiation (at sites distant from a tumour) can inhibit the normal state of surveillance against skin cancers, such that tumours progress when they might otherwise regress due to active immune attack. The idea here is that not only can UVR induce genetic change directly, but that UVR induced immunosuppression inhibits the normal process by which the immune system detects and destroys early tumours. UVR is thus carcinogenic for more than one reason—it causes mutations, and it inhibits the normal host immune defences.
Whether there is an analogous UVR influenced immunosurveillance operating in man is unclear. However, patients who are receiving systemic immunosuppressives such as the regimens employed after organ transplants (e.g. heart, kidney or liver) do show a greatly increased risk of NMSC. Whether this increase really is due to decreased immunosurveillance is not known for certain. There are other possible explanations. For instance organ transplant recipients tend to develop other tumours which are known to be associated with viral infections such as human papilloma virus associated cervical cancer and some types of Epstein Barr associated lymphomas . It is therefore possible that the immunosuppression facilitates an oncogenic role of such viruses. Finally, some drugs historically used as part of an immunosuppressive regimen such as azathioprine, seem to directly increase the mutagenic effect of UVR. Therefore, although the exact mechanisms are unclear, the practical clinical point is that certain immunosuppressive regimens used to prevent organ rejection in transplant patients are potent causes of NMSC and to a lesser degree melanoma.
- It is also thought that ultraviolet radiation may act as tumour promoter— that is an
agent that can encourage clonal expansion of clones of cells that already harbour some genetic change.
- Tumour suppressor genes are genes which act to ‘suppress’ the malignant phenotype. The key point here is that they tend to be recessive at the cellular level, whereas genes that are oncogenes are dominant at the cellular level. For reasons that I will not go into here, inherited cancer syndromes tend to involve tumour suppressors rather than oncogenes. Examples would include p53 (Li-Fraumeni syndrome), and retinoblastoma, and for basal cell carcinoma Gorlin’s syndrome (discussed later on)
- Human papilloma virus (HPV). Whereas for cervical cancer there is good evidence that certain HPVs are carcinogenic (and that vaccination against them is expected to reduce cancer incidence) the role of HPV in skin cancer remains less well understood. The problem is to know whether the HPVs that are found in NMSC are causally related to cancer development or just present more commonly because of the immunosuppression, just as the presence of benign warts is increased in organ transplant patients.
- What is meant by the statement that UVR is a tumour promoter?
- Are tumour suppressor genes dominant or recessive?
- What is meant by immunosurveillance?
- Name two types of genetic change important in skin cancer
- Is HPV relevant to skin cancer?
(answers are found at the end of the book)